Novel Oxabispidine Compounds And Their Use In The Treatment Of Cardiac Arrhythmias

ABSTRACT

There is provided compounds of formula I, wherein R 1 , R 2 , R 4 , R 41  to R 46 , A, B and G have meanings given in the description, which are useful in the prophylaxis and in the treatment of arrhythmias, in particular atrial and ventricular arrhythmias.

FIELD OF THE INVENTION

This invention relates to novel pharmaceutically useful compounds, inparticular compounds which are useful in the treatment of cardiacarrhythmias.

BACKGROUND AND PRIOR ART

Cardiac arrhythmias may be defined as abnormalities in the rate,regularity, or site of origin of the cardiac impulse or as disturbancesin conduction which causes an abnormal sequence of activation.Arrhythmias may be classified clinically by means of the presumed siteof origin (i.e. as supraventricular, including atrial andatrioventricular, arrhythmias and ventricular arrhythmias) and/or bymeans of rate (i.e. bradyarrhythmias (slow) and tachyarrhythmias(fast)).

In the treatment of cardiac arrhythmias, the negative outcome inclinical trials (see, for example, the outcome of the Cardiac ArrhythmiaSuppression Trial (CAST) reported in New England Journal of Medicine,321, 406 (1989)) with “traditional” antiarrhythmic drugs, which actprimarily by slowing the conduction velocity (class I antiarrhythmicdrugs), has prompted drug development towards compounds whichselectively delay cardiac repolarization, thus prolonging the QTinterval. Class III antiarrhythmic drugs may be defined as drugs whichprolong the trans-membrane action potential duration (which can becaused by a block of outward K⁺ currents or from an increase of inwardion currents) and refractoriness, without affecting cardiac conduction.

One of the key disadvantages of hitherto known drugs which act bydelaying repolarization (class III or otherwise) is that they all areknown to exhibit a unique form of proarrhythmia known as torsades depointes (turning of points), which may, on occasion be fatal. From thepoint of view of safety, the minimisation of this phenomenon (which hasalso been shown to be exhibited as a result of administration ofnon-cardiac drugs such as phenothiazines, tricyclic antidepressants,antihistamines and antibiotics) is a key problem to be solved in theprovision of effective antiarrhythmic drugs.

Antiarrhythmic drugs based on bispidines(3,7-diazabicyclo[3.3.1]nonanes), are known from inter aliainternational patent applications WO 91/07405 and WO 99/31100, Europeanpatent applications 306 871, 308 843 and 655 228 and U.S. Pat. Nos.3,962,449, 4,556,662, 4,550,112, 4,459,301 and 5,468,858, as well asjournal articles including, inter alia, J. Med. Chem. 39, 2559, (1996),Pharmacol. Res., 24, 149 (1991), Circulation, 90, 2032 (1994) and Anal.Sci. 9, 429, (1993).

Certain oxabispidine compounds are disclosed as chemical curiosities inChem. Ber., 96, 2872 (1963). The use of certain other oxabispidinecompounds in the treatment of cardiac arrhythmias is disclosed in WO01/28992. Methods for the preparation of such oxabispidine compounds aredisclosed in WO 02/28863, WO 02/28864, WO 02/83690 and WO 02/83691.Oxabispidine compounds of formula I, as defined below, are neitherdisclosed nor suggested by any of these documents.

We have surprisingly found that a novel group of oxabispidine-basedcompounds exhibit electrophysiological activity, and are thereforeexpected to be useful in the treatment of cardiac arrhythmias. The novelgroup of oxabispidine-based compounds has advantageous propertiescompared to compounds of the prior art, such as enhanced potency,enhanced selectivity, and/or reduction of total clearance. Theseadvantageous properties can distinguish the use of such compounds aspharmaceutical agents by lowering the daily clinical dose, lengtheningthe duration of action, and/or improving the side effect profile.

DISCLOSURE OF THE INVENTION

According to the invention there is provided compounds of formula I,

whereinR¹ represents C₁₋₁₂ alkyl (which alkyl group is optionally substitutedby one or more groups selected from halo, cyano, nitro, aryl, Het¹,—C(O)R^(5a), —OR^(5b), —N(R⁶)R^(5c), C(O)XR⁷, —C(O)N(R^(8a))R^(5d),—OC(O)N(R^(8b))R^(5e), —S(O)₂R^(9a), —S(O)₂N(R^(9b))R^(9c) and—N(R^(9b))S(O)₂R^(9d)) or R¹ represents —C(O)XR⁷, C(O)N(R^(8a))R^(5d) or—S(O)₂R^(9a);R^(5a) to R^(5e) independently represent, at each occurrence when usedherein, H, C₁₋₆ alkyl (which latter group is optionally substituted byone or more substituents selected from —OH, halo, cyano, nitro, aryl,aryloxy, Het², —S(O)₂N(R^(9b))R^(9c) and —N(R^(9b))S(O)₂R^(9d)), aryl orHet³, or R^(5d) or R^(5e), together with, respectively, R^(8a) orR^(8b), may represent C₃₋₆ alkylene (which alkylene group is optionallyinterrupted by an O atom and/or is optionally substituted by one or moreC₁₋₃ alkyl groups);R⁶ represents H, C₁₋₆ alkyl (optionally substituted by one or moresubstituents selected from —OH, halo, cyano, nitro, aryl,—S(O)₂N(R^(9b))R^(9c) and —N(R^(9b))S(O)₂R^(9d)), aryl, —C(O)R^(10a),—C(O)OR^(10b), C(O)N(R^(10c))R^(10d) or —S(O)₂R^(10e);R^(10a) to R^(10e) independently represent C₁₋₆ alkyl (optionallysubstituted by one or more substituents selected from —OH, halo, cyano,nitro and aryl), aryl, or R^(10a), R^(10c) or R^(10d) represents H;R⁷ represents, at each occurrence when used herein, C₁₋₁₂ alkyl(optionally substituted by one or more substituents selected from —OH,halo, cyano, nitro, aryl, C₁₋₆ alkoxy, Het⁴, —S(O)₂N(R^(9b))R^(9c) and—N(R^(9b))S(O)₂R^(9d));R^(8a) and R^(8b) independently represent H, C₁₋₁₂ alkyl, C₁₋₆ alkoxy(which latter two groups are optionally substituted by one or moresubstituents selected from —OH, halo, cyano, nitro, C₁₋₄ alkyl, C₁₋₄alkoxy, —S(O)₂N(R^(9b))R^(9c) and —N(R^(9b))S(O)₂R^(9d)), -D-aryl,-D-aryloxy, -D-Het⁵, -D-N(H)C(O)R^(11a), -D-S(O)₂R^(12a), D-C(O)R^(11b),-D-C(O)OR^(12b), -D-C(O)N(R^(11c))R^(11d), or R^(8a) or R^(8b), togetherwith, respectively, R^(5d) or R^(5e), may represent C₃₋₆ alkylene (whichalkylene group is optionally interrupted by an O atom and/or isoptionally substituted by one or more C₁₋₃ alkyl groups);R^(11a) to R^(11d) independently represent H, C₁₋₆ alkyl (optionallysubstituted by one or more substituents selected from —OH, halo, cyano,nitro and aryl), aryl, or R^(11c) and R^(11d) together represent C₃₋₆alkylene;R^(12a) and R^(12b) independently represent C₁₋₆ alkyl (optionallysubstituted by one or more substituents selected from —OH, halo, cyano,nitro and aryl) or aryl;D represents, at each occurrence when used herein, a direct bond or C₁₋₆alkylene;X represents O or S;R^(9a) represents, at each occurrence when used herein, C₁₋₆ alkyl(optionally substituted by one or more substituents selected from —OH,halo, cyano, nitro, aryl, —S(O)₂N(R^(9b))R^(9c) and—N(R^(9b))S(O)₂R^(9d)) or aryl;R^(9b) represents, at each occurrence when used herein, H or C₁₋₆ alkyl;R^(9c) and R^(9d) independently represent, at each occurrence when usedherein, C₁₋₆ alkyl (optionally substituted by one or more substituentsselected from —OH, halo, cyano, nitro, aryl and Het⁶), aryl or Het⁷, orR^(9c) represents H;R² represents —S(O)₂R^(3a), C(O)OR^(3b), —C(O)R^(3c),C(O)N(R^(3d))(R^(3e)) or —S(O)₂N(R^(3f))(R^(3g));R^(3a) to R^(3g) independently represent C₁₋₆ alkyl (optionallysubstituted by one or more substituents selected from halo, -E-aryl,-E-Het⁸, —C(O)R^(16a), —C(O)OR^(16b) and —C(O)N(R^(16c))R^(16d)), arylor Het⁹, or R^(3c) and R^(3d) to R^(3g) independently represent H;R^(16a) to R^(16d) independently represent, at each occurrence when usedherein, H, C₁₋₆ alkyl (optionally substituted by one or moresubstituents selected from halo, aryl and Het¹⁰), aryl, Het¹¹, orR^(16c) and R^(16d) together represent C₃₋₆ alkylene, optionallyinterrupted by an O atom;E represents, at each occurrence when used herein, a direct bond or C₁₋₄alkylene;

Het¹ to Het¹¹ independently represent five- to twelve-memberedheterocyclic groups containing one or more heteroatoms selected fromoxygen, nitrogen and/or sulfur, which groups are optionally substitutedby one or more substituents selected from —OH, oxo, halo, cyano, nitro,C₁₋₆ alkyl, C₁₋₆ alkoxy, aryl, aryloxy, N(R^(17a))R^(17b), C(O)R^(17c),C(O)OR^(17d), —C(O)N(R^(17e))R^(17f), —N(R^(17g))C(O)R^(17h),—S(O)₂N(R^(17i))R^(17j) and —N(R^(17k))S(O)₂R^(17l);

R^(17a) to R^(17l) independently represent C₁₋₆ alkyl, aryl or R^(17a)to R^(17k) independently represent H;A represents C₂₋₆ alkylene optionally interrupted by —S(O)₂N(R^(18a))—or —N(R^(18b))S(O)₂— and/or optionally substituted by one or moresubstituents selected from —OH, halo and amino;B represents -Z¹-{[C(O)]_(a)C(H)(R^(19a))}_(b)—,-Z²-[C(O)]_(c)N(R^(19b))—, -Z²-S(O)_(n)—, -Z²-N(R^(18c))S(O)₂—,-Z²-S(O)₂N(R^(18d))— or -Z²-O— (in which six groups Z¹ or Z² is attachedto the nitrogen atom bearing R²);Z¹ represents a direct bond or C₁₋₄ alkylene, optionally interrupted by—N(R^(18e))S(O)₂— or —S(O)₂N(R^(18f))—;Z² represents, at each occurrence when used herein, C₂₋₄ alkylene,optionally interrupted by —N(R^(18g))S(O)₂— or —S(O)₂N(R^(18h))—;a, b and c independently represent 0 or 1;n represents 0, 1 or 2;R^(18a) to R^(18h) independently represent H or C₁₋₆ alkyl;R^(19a) represents H or, together with a single R⁴ substituent at aposition on the phenyl or pyridyl group that is ortho- to the positionat which the group B is attached, R^(19a) represents C₂₋₄ alkyleneoptionally interrupted or terminated by O, S or N(R²⁰);R^(19b) represents H, C₁₋₆ alkyl or, together with a single R⁴substituent at a position on the phenyl or pyridyl group that is ortho-to the position at which the group B is attached, R^(19b) representsC₂₋₄ alkylene;R²⁰ represents H or C₁₋₆ alkyl;G represents CH or N;R⁴ represents one or more optional substituents selected from —OH,cyano, halo, nitro, C₁₋₆ alkyl (optionally terminated by—N(H)C(O)OR^(21a)), C₁₋₆ alkoxy, —N(R^(22a))R^(22b), —C(O)R^(22c),C(O)OR^(22d), C(O)N(R^(22e))R^(22f), —N(R^(22g))C(O)R^(22h),—N(R^(22i))C(O)N(R^(22j))R^(22k), —N(R^(22m))S(O)₂R^(21b),—S(O)₂N(R^(22a))R^(22o), —S(O)₂R^(21c), —OS(O)₂R^(21d) and aryl,and an R⁴ substituent in a position on the phenyl or pyridyl group thatis ortho- to the position at which the group B is attached may

-   -   (i) together with R^(19a), represent C₂₋₄ alkylene optionally        interrupted or terminated by O, S or N(R^(20c)), or    -   (ii) together with R^(19b), represent C₂₋₄ alkylene;        R^(21a) to R^(21d) independently represent C₁₋₆ alkyl;        R^(22a) and R^(22b) independently represent H, C₁₋₆ alkyl or        together represent C₃₋₆ alkylene, resulting in a four- to        seven-membered nitrogen-containing ring;        R^(22c) to R^(22o) independently represent H or C₁₋₆ alkyl; and        R⁴¹ to R⁴⁶ independently represent H or C₁₋₃ alkyl;        wherein each aryl and aryloxy group, unless otherwise specified,        is optionally substituted;        or a pharmaceutically acceptable derivative thereof;        which compounds are referred to hereinafter as “the compounds of        the invention”.

For the avoidance of doubt it is to be understood that where in thisspecification a group is qualified by ‘hereinbefore defined’, ‘definedhereinbefore’ or ‘defined above’ the said group encompasses the firstoccurring and broadest definition as well as each and all of the otherdefinitions for that group.

Unless otherwise specified, alkyl groups and alkoxy groups as definedherein may be straight-chain or, when there is a sufficient number (i.e.a minimum of three) of carbon atoms be branched-chain, and/or cyclic.Further, when there is a sufficient number (i.e. a minimum of four) ofcarbon atoms, such alkyl and alkoxy groups may also be partcyclic/acyclic. Such alkyl and alkoxy groups may also be saturated or,when there is a sufficient number (i.e. a minimum of two) of carbonatoms, be unsaturated and/or interrupted by one or more oxygen and/orsulfur atoms. Unless otherwise specified, alkyl and alkoxy groups mayalso be substituted by one or more halo, and especially fluoro, atoms.

Unless otherwise specified, alkylene groups as defined herein may bestraight-chain or, when there is a sufficient number (i.e. a minimum oftwo) of carbon atoms, be branched-chain. Such alkylene chains may alsobe saturated or, when there is a sufficient number (i.e. a minimum oftwo) of carbon atoms, be unsaturated and/or interrupted by one or moreoxygen and/or sulfur atoms. Unless otherwise specified, alkylene groupsmay also be substituted by one or more halo atoms.

The term “aryl”, when used herein, includes C₆₋₁₀ aryl groups such asphenyl, naphthyl and the like. The term “aryloxy”, when used hereinincludes C₆₋₁₀ aryloxy groups such as phenoxy, naphthoxy and the like.For the avoidance of doubt, aryloxy groups referred to herein areattached to the rest of the molecule via the O-atom of the oxy-group.Unless otherwise specified, aryl and aryloxy groups may be substitutedby one or more substituents including —OH, halo, cyano, nitro, C₁₋₆alkyl, C₁₋₆ alkoxy, N(R^(22a))R^(22b), —C(O)R^(22c), —C(O)OR^(22d),C(O)N(R^(22e))R^(22f), —N(R^(22g))C(O)R^(22h), —N(R^(22m))S(O)₂R^(21b),—S(O)₂N(R^(22n))R^(22o), —S(O)₂R^(21c), and/or —OS(O)₂R^(21d) (whereinR^(21b) to R^(21d) and R^(22a) to R^(22o) are as hereinbefore defined).When substituted, aryl and aryloxy groups are preferably substituted bybetween one and three substituents.

The term “halo”, when used herein, includes fluoro, chloro, bromo andiodo.

Het (Het¹, Het², Het³, Het⁴, Het⁵, Het⁶, Het⁷, Het⁸, Het⁹, Het¹⁰ andHet¹¹) groups that may be mentioned include those containing 1 to 4heteroatoms (selected from the group oxygen, nitrogen and/or sulfur) andin which the total number of atoms in the ring system are between fiveand twelve. Het (Het¹, Het², Het³, Het⁴, Het⁵, Het⁶, Het⁷, Het⁸, Het⁹,Het¹⁰ and Het¹¹) groups may be fully saturated, wholly aromatic, partlyaromatic and/or bicyclic in character. Heterocyclic groups that may bementioned include 1-azabicyclo[2.2.2]octanyl, benzimidazolyl,benzisoxazolyl, benzodioxanyl, benzodioxepanyl, benzodioxolyl,benzofuranyl, benzofurazanyl, benzomorpholinyl, 2,1,3-benzoxadiazolyl,benzoxazinonyl, benzoxazolidinyl, benzoxazolyl, benzopyrazolyl,benzo[e]pyrimidine, 2,1,3-benzothiadiazolyl, benzothiazolyl,benzothienyl, benzotriazolyl, chromanyl, chromenyl, cinnolinyl,2,3-dihydrobenzimidazolyl, 2,3-dihydrobenzo[b]furanyl,1,3-dihydrobenzo[c]furanyl, 2,3-dihydropyrrolo[2,3-b]pyridinyl,dioxanyl, furanyl, hexahydropyrimidinyl, hydantoinyl, imidazolyl,imidazo[1,2-a]pyridinyl, imidazo[2,3-b]thiazolyl, indolyl,isoquinolinyl, isoxazolyl, maleimido, morpholinyl, oxadiazolyl,1,3-oxazinanyl, oxazolyl, phthalazinyl, piperazinyl, piperidinyl,purinyl, pyranyl, pyrazinyl, pyrazolyl, pyridinyl, pyrimidinyl,pyrrolidinonyl, pyrrolidinyl, pyrrolinyl, pyrrolo[2,3-b]pyridinyl,pyrrolo[5,1-b]pyridinyl, pyrrolo[2,3-c]pyridinyl, pyrrolyl,quinazolinyl, quinolinyl, sulfolanyl, 3-sulfolenyl,4,5,6,7-tetrahydrobenzimidazolyl, 4,5,6,7-tetrahydrobenzopyrazolyl,5,6,7,8-tetrahydrobenzo[e]-pyrimidine, tetrahydrofuranyl,tetrahydropyranyl, 3,4,5,6-tetrahydropyridinyl,1,2,3,4-tetrahydropyrimidinyl, 3,4,5,6-tetrahydropyrimidinyl,thiadiazolyl, thiazolidinyl, thiazolyl, thienyl, thieno[5,1-c]pyridinyl,thiochromanyl, triazolyl, 1,3,4-triazolo[2,3-b]pyrimidinyl and the like.

Values of Het¹ that may be mentioned include 2,3-dihydrobenzo[b]furanyl,furanyl, imidazolyl, isoxazolyl, pyridinyl and thiazolyl.

Substituents on Het (Het¹, Het², Het³, Het⁴, Het⁵, Het⁶, Het⁷, Het⁸,Het⁹, Het¹⁰ and Het¹¹) groups may, where appropriate, be located on anyatom in the ring system including a heteroatom. The point of attachmentof Het (Het¹, Het², Het³, Het⁴, Het⁵, Het⁶, Het⁷, Het⁸, Het⁹, Het¹⁰ andHet¹¹) groups may be via any atom in the ring system including (whereappropriate) a heteroatom, or an atom on any fused carbocyclic ring thatmay be present as part of the ring system. Het (Het¹, Het², Het³, Het⁴,Het⁵, Het⁶, Het⁷, Het⁸, Het⁹, Het¹⁰ and Het¹¹) groups may also be in theN- or S-oxidised form.

Pharmaceutically acceptable derivatives include salts and solvates.Salts which may be mentioned include acid addition salts.Pharmaceutically acceptable derivatives also include, at theoxabispidine or (when G represents N) pyridyl nitrogens, C₁₋₄ alkylquaternary ammonium salts and N-oxides, provided that when a N-oxide ispresent:

-   (a) no Het (Het¹, Het², Het³, Het⁴, Het⁵, Het⁶, Het⁷, Het⁸, Het⁹,    Het¹⁰ and Het¹¹) group contains an unoxidised S-atom; and/or-   (b) n does not represent 0 when B represents -Z²-S(O)_(n)—.

The compounds of the invention may exhibit tautomerism. All tautomericforms and mixtures thereof are included within the scope of theinvention.

The compounds of the invention may also contain one or more asymmetriccarbon atoms and may therefore exhibit optical and/ordiastereoisomerism.

Diastereoisomers may be separated using conventional techniques, e.g.chromatography or fractional crystallisation. The various stereoisomersmay be isolated by separation of a racemic or other mixture of thecompounds using conventional, e.g. fractional crystallisation or HPLC,techniques. Alternatively the desired optical isomers may be made byreaction of the appropriate optically active starting materials underconditions which will not cause racemisation or epimerisation, or byderivatisation, for example with a homochiral acid followed byseparation of the diastereomeric esters by conventional means (e.g.HPLC, chromatography over silica). All stereoisomers are included withinthe scope of the invention.

Abbreviations are listed at the end of this specification.

Preferred values of each variable group are as follows. Such values maybe used where appropriate with any of the values, definitions, claims,aspects or embodiments defined hereinbefore or hereinafter. Inparticular, each may be used as an individual limitation on the broadestdefinition of formula (I).

Particular values of each variable group are as follows. Such values maybe used where appropriate with any of the values, definitions, claims,aspects or embodiments defined hereinbefore or hereinafter. Inparticular, each may be used as an individual limitation on the broadestdefinition of formula (I). R¹ represents C₁₋₄ alkyl, which alkyl groupis substituted by at least one-phenyl or phenoxy group (both optionallysubstituted by one or more halo, cyano, methyl, methoxy, fluoromethoxy,difluoromethoxy or trifluoromethoxy groups);

A represents a direct bond or C₁₋₃ alkylene (such as a C₂ alkylene);B represents a direct bond, C₁₋₃ alkylene (such as a C₂ alkylene), orC₁₋₃ alkoxy (such as a C₂ alkoxy, in which the oxygen is attached to thephenyl group that is optionally substituted with R⁴);R² represents —S(O)₂R^(3a), —C(O)OR^(3b), —C(O)R^(3c) orC(O)N(R^(3d))R^(3e);R^(3a) to R^(3b) each independently represent hydrogen or C₁₋₃ alkyl(such as methyl, ethyl, isopropyl or propyl);G represents carbon;R⁴¹ to R⁴⁶ represents hydrogen; andR⁴ represents one or more optional substituents selected from cyanoand/or halo (such as fluoro) and an R⁴ substituent is in a position onthe phenyl group that is ortho- and/or para- to the position at whichthe group B is attached.

Preferred compounds of the invention include those in which:

R¹ represents C₁₋₈ alkyl (which alkyl group is optionally substituted byone or more groups selected from halo, aryl (which latter group isoptionally substituted by one or more substituents selected from —OH,halo, cyano, nitro, C₁₋₅ alkyl, C₁₋₄ alkoxy (which latter two groups areoptionally substituted by one or more halo atoms), —C(O)R^(22c) and—S(O)₂R^(21c)), Het¹, —C(O)R^(5a), —OR^(5b), —N(R⁶)R^(5c),C(O)N(R^(8a))R^(5d), —OC(O)N(R^(8b))R^(5e), —S(O)₂R^(9a),—S(O)₂N(H)R^(9c) and —N(H)S(O)₂R^(9d)) or R¹ represents —C(O)OR⁷,—C(O)N(R^(8a))R^(5d) or —S(O)₂R^(9a);R^(5a) to R^(5e) independently represent, at each occurrence when usedherein, H, C₁₋₆ alkyl (which latter group is optionally substituted byone or more substituents selected from cyano, nitro, optionallysubstituted aryl and optionally substituted aryloxy), aryl (which lattergroup is optionally substituted by one or more substituents selectedfrom —OH, halo, cyano, nitro, N(R^(22a))R^(22b) (in which latter groupR^(22a) and R^(22b) together represent C₃₋₆ alkylene), C₁₋₅ alkyl andC₁₋₅ alkoxy (which latter two groups are optionally substituted by oneor more halo atoms)), Het³, or R^(5d), together with R^(8a), representsC₄₋₅ alkylene (which alkylene group is optionally interrupted by an Oatom);R⁶ represents H, C₁₋₆ alkyl, optionally substituted aryl —C(O)R^(10a),—C(O)OR^(10b), —C(O)N(R^(10c))R^(10d) or —S(O)₂R^(10e);R^(10a), R^(10b) and R^(10e) independently represent C₁₋₅ alkyl(optionally substituted by one or more substituents selected from haloand optionally substituted aryl) or optionally substituted aryl;R^(10c) and R^(10d) independently represent H or C₁₋₄ alkyl;R⁷ represents C₁₋₆ alkyl (optionally substituted by one or moresubstituents selected from halo, optionally substituted aryl, C₁₋₄alkoxy and Het⁴);R^(8a) and R^(8b) independently represent H, C₁₋₆ alkyl (which lattergroup is optionally substituted by one or more substituents selectedfrom halo, cyano and nitro), -D-(optionally substituted aryl),-D-(optionally substituted aryloxy), -D-Het⁵, -D-N(H)C(O)R^(11a),-D-C(O)R^(11b), or R^(8a), together with R^(5d) represents C₄₋₅ alkylene(which alkylene group is optionally interrupted by an O atom);R^(11a) and R^(11d) independently represent C₁₋₄ alkyl (optionallysubstituted by one or more substituents selected from halo, cyano, nitroand optionally substituted aryl) or optionally substituted aryl;D represents, at each occurrence when used herein, a direct bond or C₁₋₄alkylene;R^(9a) represents, C₁₋₆ alkyl (optionally substituted by one or morehalo groups) or optionally substituted aryl;R^(9c) and R^(9d) independently represent, at each occurrence when usedherein, C₁₋₅ alkyl (optionally substituted by one or more substituentsselected from halo, optionally substituted aryl and Het⁶), optionallysubstituted aryl or Het⁷, or R^(9c) represents H;R² represents —S(O)₂R^(3a), —C(O)OR^(3b), —C(O)R^(3c) or—C(O)N(R^(3d))R^(3e);R^(3a) to R^(3e) independently represent C₁₋₅ alkyl (optionallysubstituted by one or more substituents selected from halo, optionallysubstituted aryl and Het⁸), optionally substituted aryl or Het⁹, orR^(3d) represents H;Het¹ and Het³ to Het⁹ independently represent four- to ten-memberedheterocyclic groups containing one to four heteroatoms selected fromoxygen, nitrogen and/or sulfur, which groups are optionally substitutedby one or more substituents selected from —OH, oxo, halo, cyano, C₁₋₄alkyl, C₁₋₄ alkoxy, phenyl, —N(H)R^(17a), —C(O)R^(17c), —N(H)C(O)R^(17h)and —N(H)S(O)₂R^(17j);R^(17a), R^(17c), R^(17h) and R^(17j) independently represent C₁₋₄ alkylor optionally substituted aryl or R^(17a), R^(17c) and R^(17h)independently represent H;A represents C₂₋₄ alkylene optionally substituted by one or moresubstituents selected from —OH and amino;B represents -Z¹-, -Z²-N(H)—, -Z²-C(O)N(R^(19b))—, -Z²-S(O)₂—,-Z²-N(H)S(O)₂—, -Z²-S(O)₂N(H)— or -Z²-O— (in which latter six groups, Z²is attached to the nitrogen atom bearing R²);Z¹ represents a direct bond or C₁₋₄ alkylene;Z² represents C₂₋₄ alkylene;R^(19b) represents H, C₁₋₄ alkyl, or, together with a single R⁴substituent at a position on the phenyl or pyridyl group that is ortho-to the position at which the group B is attached, R^(19b) representsC₂₋₄ alkylene;when G represents N, G is in the ortho- or, in particular, thepara-position relative to the point of attachment of B;when G represents N, R⁴ is absent or represents a single cyano group;R⁴ is absent (i.e. represents H) or represents one or more substituentsselected from —OH, cyano, halo, nitro, C₁₋₆ alkyl, C₁₋₆ alkoxy,—C(O)N(R^(22e))R^(22f), and —N(R^(22m))S(O)₂—C₁₋₄ alkyl, or an R⁴substituent in a position on the phenyl or pyridyl group that is ortho-to the position at which the group B is attached may, together withR^(19b), represent C₂₋₄ alkylene;R^(21c) represents C₁₋₄ alkyl;R^(22c), R^(22e), R^(22f) and R^(22m) independently represent H or C₁₋₄alkyl;R⁴¹ to R⁴⁶ independently represent H;optional substituents on aryl and aryloxy groups are, unless otherwisestated, one or more substituents selected from halo, cyano, nitro, C₁₋₄alkyl, C₁₋₄ alkoxy (which latter two groups are optionally substitutedby one or more halo atoms), —N(H)S(O)₂R^(21b) and —S(O)₂N(H)R^(22o).

More preferred compounds of the invention include those in which:

R¹ represents straight- or branched-chain or part cyclic/acyclic C₁₋₆alkyl, which alkyl group is optionally interrupted by oxygen and/orsubstituted by: (i) one or more halo or OR^(5b) groups; and/or (ii) onegroup selected from phenyl (which latter group is optionally substitutedby one or more (e.g. one to three) substituents selected from halo,cyano, C₁₋₄ alkyl, C₁₋₃ alkoxy (which latter two groups are optionallysubstituted by one or more halo (e.g. fluoro) atoms), —C(O)—C₁₋₃ alkyland —S(O)₂—C₁₋₄ alkyl), Het¹, —C(O)R^(5a), —N(R⁶)R^(5c),—C(O)N(R^(8a))R^(5d), —OC(O)N(H)R^(8b) and —S(O)₂—C₁₋₄ alkyl, or R¹represents —C(O)OR⁷, —C(O)N(R^(8a))R^(5d) or —S(O)₂—C₁₋₅ alkyl;Het¹ represents a four- (e.g. five-) to ten-membered heterocyclic groupcontaining one to three heteroatoms selected from oxygen, nitrogenand/or sulfur, which group is optionally substituted by one or more(e.g. one to three) substituents selected from halo, C₁₋₃ alkyl, C₁₋₃alkoxy and —C(O)—C₁₋₄ alkyl;R^(5a), R^(5b) and R^(5d) independently represent H, C₁₋₅ alkyl, phenyl(which latter group is optionally substituted by one or moresubstituents selected from —OH, halo, cyano, pyrrolidin-1-yl, C₁₋₄ alkyland C₁₋₅ alkoxy (which latter group is optionally substituted by one ormore halo (e.g. fluoro) atoms)) or Het³;R^(5c) represents H or C₁₋₅ alkyl (optionally substituted by phenyl orphenoxy, which latter two groups are optionally substituted by one tothree substituents selected from halo, cyano and C₁₋₂ alkyl);Het³ represents a five- to ten-membered heterocyclic group containingone or two heteroatoms selected from oxygen and nitrogen, which group isoptionally substituted by one or more substituents selected from oxo,C₁₋₂ alkyl and —C(O)—C₁₋₄ alkyl;R⁶ represents H, C₁₋₄ alkyl, phenyl (which latter group is optionallysubstituted by one or more cyano groups), —C(O)O—C₁₋₅ alkyl,—C(O)N(R^(10c))R^(10d) or —S(O)₂R^(10e);R^(10c) and R^(10d) independently represent H or C₁₋₃ alkyl;R^(10e) represents C₁₋₅ alkyl (optionally substituted by one or morefluoro atoms) or phenyl (optionally substituted by one or moresubstituents selected from halo, C₁₋₃ alkyl and C₁₋₃ alkoxy);R⁷ represents C₁₋₅ alkyl optionally substituted by Het⁴;Het⁴ represents a five- to ten-membered heterocyclic group containingone or two heteroatoms selected from oxygen and nitrogen, which group isoptionally substituted by one or more substituents selected from C₁₋₂alkyl and —C(O)—C₁₋₄ alkyl;R^(8a) and R^(8b) independently represent H, C₁₋₅ alkyl or -D-(phenyl),the phenyl part of which latter group is optionally substituted by oneor more (e.g. one to three) substituents selected from halo, C₁₋₃ alkyland C₁₋₃ alkoxy;D represents C₁₋₃ alkylene (e.g. CH₂ or C(CH₃)₂);R² represents —S(O)₂R^(3a) or —C(O)N(R^(3d))R^(3e);R^(3a) represents C₁₋₄ alkyl (optionally substituted by phenyl or one ormore halo (e.g. fluoro) atoms), phenyl (which latter group is optionallysubstituted by or more (e.g. one to three) substituents selected fromhalo, C₁₋₃ alkyl and C₁₋₃ alkoxy) or Het⁹;Het⁹ represents a five- to ten-membered heterocyclic group containingone to three heteroatoms selected from oxygen, nitrogen and/or sulfur,which group is optionally substituted by one to three substituentsselected from halo, C₁₋₂ alkyl and C₁₋₂ alkoxy;R^(3d) and R^(3e) independently represent H or C₁₋₃ alkyl (which lattergroup is by phenyl or one or more halo (e.g. fluoro) atoms), phenyl(which latter group is optionally substituted by or more (e.g. one tothree) substituents selected from halo, C₁₋₃ alkyl and C₁₋₃ alkoxy);A represents C₂ n-alkylene or C₃ n-alkylene, which latter group isoptionally substituted, in the 2-position relative to the point ofattachment to the oxabispidine N-atom, by —OH;B represents -Z¹-, -Z²-N(H)—, -Z²-C(O)N(R^(19b))—, -Z²-S(O)₂— or -Z²-O—(in which latter four groups, Z² is attached to the nitrogen atombearing R²);Z¹ represents C₁₋₄ alkylene;Z² represents C₂₋₃ alkylene;R^(19b), together with a single R⁴ substituent at a position on thephenyl or pyridyl group that is ortho- to the position at which thegroup B is attached, represents C₂₋₃ alkylene;G represents CH;R⁴ is absent (i.e. represents H) or represents one or two cyano groupsin the ortho- and/or, particularly, the para-position relative to thepoint of attachment of the group B, or alternatively, when B represents-Z²-C(O)N(R^(19b))—,

-   -   (i) an R⁴ substituent in a position on the phenyl or pyridyl        group that is ortho- to the position at which the group B is        attached may, together with R^(19b), represent C₂₋₃ alkylene,        and    -   (ii) R⁴ may further represent a nitro group in the para-position        relative to the point of attachment of the group B.

Particular compounds of the invention include, for example, compounds ofthe Formula I, or pharmaceutically-acceptable salts thereof, wherein,unless otherwise stated, each of each variable group has any of themeanings defined hereinbefore or in paragraphs (a) to (d) hereinafter:—

-   -   (a) R¹ represents a C₁-C₅ alkyl group, (such as methyl, ethyl,        propyl, butyl, propyl or pentyl), which is optionally        substituted by a group selected from phenyl, 2-cyanophenyl,        4-cyanophenyl, 2,4-dicyanophenyl, 2,6-dimethylphenyl,        3-methoxyphenyl, 4-methoxyphenyl, 4-acetylphenyl,        2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 4-chlorophenyl,        2,4-difluorophenyl, 3-pyridine, 4-pyridine, 2-chloro-3-pyridine,        6-methoxy-3-pyridine, 2,6-dichloro-4-pyridine,        4,5-dimethyl-2-furane, 3-trifluoromethylphenyl,        4-trifluoromethylphenyl, 4-chlorophenyl,        4-(difluoromethoxy)phenyl, 4-(methylsulfonyl)phenyl,        2,5-dichlorophenyl, 3,5-dimethyl-4-isoxazole,        2,4-dimethyl-5-(1,3-thiazole), (1-methyl-2-(1H-imidazole),        2,6-dimethylphenyl, 4-tert-butylphenyl, or        2-fluoro-4-(trifluoromethyl)phenyl; and/or optionally        interrupted or terminated by an oxygen atom;    -   (b) R⁴¹ to R⁴⁶ are hydrogen;    -   (c) R² represents methylsulfonyl, aminocarbonyl,        N,N-dimethylaminocarbonyl, phenylsulfonyl, ethylsulfonyl,        N-methylaminocarbonyl, trifluoromethylsulfonyl, acetyl, or        isopropylsulfonyl;    -   (d) the group

represents phenyl, 2-cyanophenyl, 3-cyanophenyl, 4-cyanophenyl,2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl,4-(difluoromethoxy)phenyl, 2-chlorophenyl, 3-chlorophenyl, or4-chlorophenyl.

Particularly preferred compounds of the invention include those inwhich:

R¹ represents straight- or branched-chain or part cyclic/acyclic C₁₋₆alkyl, which alkyl group is optionally interrupted by oxygen and/orsubstituted by: (i) one or more halo or OR^(5b) groups; and/or (ii) onegroup selected from phenyl (which latter group is optionally substitutedby one or more (e.g. one to three) substituents selected from halo,cyano, C₁₋₄ alkyl (e.g. methyl or C₄ alkyl such as tert-butyl), C₁₋₂alkoxy (which C₁₋₄ alkyl and C₁₋₂ alkoxy groups are optionallysubstituted by one or more halo (e.g. fluoro) atoms), —C(O)—C₁₋₂ alkyland —S(O)₂—C₁₋₂ alkyl), Het¹, —C(O)R^(5a), —N(R⁶)R^(5c), —C(O)N(H)R^(8a)and —S(O)₂—C₁₋₄ alkyl;Het¹ represents a five- or six-membered heterocyclic group containingone or two heteroatoms selected from oxygen, nitrogen and/or sulfur,which group is optionally substituted by one or more (e.g. one or two)substituents selected from halo (e.g. chloro), C₁₋₂ alkyl and C₁₋₂alkoxy;R^(5a) and R^(5b) independently represent phenyl optionally substitutedby one to three substituents selected from halo, C₁₋₂ alkyl and C₁₋₂alkoxy;R^(5c) represents C₁₋₃ alkyl substituted by phenyl or phenoxy (whichlatter two groups are optionally substituted by one or two cyanogroups);R⁶ represents H, C₁₋₄ alkyl, —C(O)O—C₁₋₅ alkyl —C(O)N(R^(10c))R^(10d) or—S(O)₂R^(10e);R^(10c) and R^(10d) independently represent H or C₁₋₂ alkyl (e.g.methyl);R^(10e) represents C₁₋₃ alkyl (optionally substituted by one or morefluoro atoms);R^(8a) represents C₁₋₄ alkyl (e.g. tert-butyl) or -D-(phenyl);R² represents —S(O)₂R^(3a) or —C(O)N(R^(3d))R^(3e);R^(3a) represents C₁₋₂ alkyl (optionally substituted by phenyl or one ormore halo (e.g. fluoro) atoms);R^(3d) and R^(3e) independently represent H or C₁₋₂ alkyl (e.g. methyl);A represents C₂ or C₃ n-alkylene;B represents -Z¹- or -Z²-O— (in which latter group Z² is attached to thenitrogen atom bearing R²);Z¹ represents C₁₋₃ alkylene;Z² represents C₂₋₃ n-alkylene (e.g. C₂ n-alkylene);R⁴ is absent (i.e. represents H) or represents a cyano group in thepara-position relative to the point of attachment of the group B.

Especially preferred compounds of the invention include those in which:

R¹ represents straight- or branched-chain C₁₋₃ alkyl substituted byOR^(5b), phenyl (which latter group is optionally substituted by one ortwo substituents selected from halo (e.g. fluoro or chloro), cyano,tert-butyl, methyl, methoxy (which latter two groups are optionallysubstituted by one to three fluoro atoms), —C(O)CH₃ and —S(O)₂CH₃),Het¹, C(O)R^(5a), —N(R⁶)R^(5c), —N(H)C₃₋₄ alkyl or —C(O)N(H)R^(8a);Het¹ represents an aromatic five- or six-membered heterocyclic groupcontaining one or two heteroatoms selected from oxygen, nitrogen and/orsulfur, which group is optionally substituted by one or two substituentsselected from chloro, methyl and methoxy;R^(5a) and R^(5b) independently represent phenyl optionally substitutedby one or two methyl or methoxy groups;R^(5c) represents H or benzyl;R⁶ represents —C(O)O—C₃₋₄ alkyl, —C(O)N(R^(10c))R^(10d) or —S(O)₂CH₃;R^(10c) and R^(10d) independently represent methyl or, preferably, H;R^(8a) represents tert-butyl, CH₂-phenyl or C(CH₃)₂-phenyl;R² represents —C(O)N(CH₃)₂, —C(O)N(H)CH₃, —C(O)NH₂, or, particularly,—S(O)₂CH₃;A represents —(CH₂)₂—;B represents —(CH₂)₁₋₃— (e.g. —CH₂— or —(CH₂)₃—) or —(CH₂)₂—O— (in whichlatter group, the —(CH₂)₂— part is attached to the nitrogen atom bearingR²).

Preferred compounds of the invention include the compounds of theExamples disclosed hereinafter. In this respect, preferred compounds ofthe invention that might be mentioned include:

-   (i)    tert-butyl[2-(7-{2-[[2-(4-cyanophenoxy)ethyl](methylsulfonyl)-amino]ethyl}-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl)ethyl]-carbamate;-   (ii) tert-butyl    {2-[7-(2-{(aminocarbonyl)[2-(4-cyanophenoxy)ethyl]-amino}ethyl)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl]ethyl}-carbamate;-   (iii)    N-[2-(4-cyanophenoxy)ethyl]-N-(2-{7-[2-(4-methoxyphenyl)-2-oxoethyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}ethyl)methanesulfonamide;-   (iv)    N-[2-(4-cyanophenoxy)ethyl]-N-(2-{7-[2-(4-methoxyphenyl)-2-oxoethyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}ethyl)urea;-   (v)    N-[2-(7-benzyl-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl)ethyl]-N-[2-(4-cyanophenoxy)ethyl]methanesulfonamide;-   (vi)    N-[2-(7-benzyl-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl)ethyl]-N-[2-(4-cyanophenoxy)ethyl]urea;-   (vii)    2-[7-(2-{(aminocarbonyl)[2-(4-cyanophenoxy)ethyl]amino}ethyl)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl]-N-(tert-butyl)acetamide;-   (viii)    2-[7-(2-{(aminocarbonyl)[2-(4-cyanophenoxy)ethyl]amino}ethyl)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl]-N-benzylacetamide;-   (ix)    2-[7-(2-{(aminocarbonyl)[2-(4-cyanophenoxy)ethyl]amino}ethyl)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl]-N-(1-methyl-1-phenylethyl)acetamide;-   (x) N-(tert-butyl)-2-(7-{2-[[2-(4-cyanophenoxy)ethyl]    (methylsulfonyl)-amino]ethyl}-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl)acetamide;-   (xi)    N-benzyl-2-(7-{2-[[2-(4-cyanophenoxy)ethyl](methylsulfonyl)-amino]ethyl}-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl)acetamide;-   (xii)    2-(7-{2-[[2-(4-cyanophenoxy)ethyl](methylsulfonyl)amino]ethyl}-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl)-N-(1-methyl-1-phenyl-ethyl)acetamide;-   (xiii)    tert-butyl[2-(7-{2-[[3-(4-cyanophenyl)propyl](methylsulfonyl)-amino]ethyl}-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl)ethyl]-carbamate;-   (xiv)    N-(tert-butyl)-2-(7-{2-[[3-(4-cyanophenyl)propyl](methylsulfonyl)-amino]ethyl}-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl)acetamide;-   (xv)    N-[2-(7-benzyl-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl)ethyl]-N-[3-(4-cyanophenyl)propyl]methanesulfonamide;-   (xvi)    N-[2-(4-cyanophenoxy)ethyl]-N-(2-{7-[2-(2,6-dimethylphenoxy)-ethyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}ethyl)urea;-   (xvii)    N-[2-(4-cyanophenoxy)ethyl]-N-(2-{7-[2-(4-cyanophenyl)ethyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}ethyl)urea;-   (xviii)    N-[2-(4-cyanophenoxy)ethyl]-N-(2-{7-[2-(4-methoxyphenyl)ethyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}ethyl)urea;-   (xix)    N-(2-{7-[2-(4-acetylphenyl)ethyl]-9-oxa-3,7-diazabicyclo-[3.3.1]non-3-yl}ethyl)-N-[2-(4-cyanophenoxy)ethyl]urea;-   (xx)    N-[2-(4-cyanophenoxy)ethyl]-N-{2-[7-(2-phenylethyl)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl]ethyl}urea;-   (xxi)    N-[2-(4-cyanophenoxy)ethyl]-N-(2-{7-[2-(3-fluorophenyl)ethyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}ethyl)urea;-   (xxii)    N-(2-{7-[(2-chloropyridin-3-yl)methyl]-9-oxa-3,7-diazabicyclo-[3.3.1]non-3-yl}ethyl)-N-[2-(4-cyanophenoxy)ethyl]methane-sulfonamide;-   (xxiii)    N-[2-(4-cyanophenoxy)ethyl]-N-(2-{7-[(6-methoxypyridin-3-yl)methyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}ethyl)methanesulfonamide;-   (xxiv)    N-[2-(4-cyanophenoxy)ethyl]-N-(2-{7-[(4,5-dimethyl-2-furyl)-methyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}ethyl)methanesulfonamide;-   (xxv)    N-[2-(4-cyanophenoxy)ethyl]-N-{2-[7-(4-fluorobenzyl)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl]ethyl}methanesulfonamide;-   (xxvi)    N-[2-(4-cyanophenoxy)ethyl]-N-(2-{7-[4-(trifluoromethyl)benzyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}ethyl)methanesulfonamide;-   (xxvii)    N-{2-[7-(4-chlorobenzyl)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl]ethyl}-N-[2-(4-cyanophenoxy)ethyl]methanesulfonamide;-   (xxviii)    N-[2-(4-cyanophenoxy)ethyl]-N-(2-{7-[4-(difluoromethoxy)-benzyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}ethyl)methanesulfonamide;-   (xxix)    N-[2-(4-cyanophenoxy)ethyl]-N-(2-{7-[4-(methylsulfonyl)benzyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}ethyl)methanesulfonamide;-   (xxx)    N-[2-(4-cyanophenoxy)ethyl]-N-{2-[7-(2-fluorobenzyl)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl]ethyl}methanesulfonamide;-   (xxxi)    N-[2-(4-cyanophenoxy)ethyl]-N-{2-[7-(2,4-difluorobenzyl)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl]ethyl}methanesulfonamide;-   (xxxii)    N-[2-(4-cyanophenoxy)ethyl]-N-{2-[7-(2,5-dichlorobenzyl)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl]ethyl}methanesulfonamide;-   (xxxiii)    N-[2-(4-cyanophenoxy)ethyl]-N-(2-{7-[3-(trifluoromethyl)benzyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}ethyl)methanesulfonamide;-   (xxxiv)    N-{2-[7-(4-cyanobenzyl)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl]ethyl}-N-[2-(4-cyanophenoxy)ethyl]methanesulfonamide;-   (xxxv)    N-{2-[7-(2-cyanobenzyl)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl]ethyl}-N-[2-(4-cyanophenoxy)ethyl]methanesulfonamide;-   (xxxvi)    N-[2-(4-cyanophenoxy)ethyl]-N-(2-{7-[(2,6-dichloropyridin-4-yl)methyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}ethyl)methanesulfonamide;-   (xxxvii)    N-[2-(4-cyanophenoxy)ethyl]-N-{2-[7-(pyridin-4-ylmethyl)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl]ethyl}methanesulfonamide;-   (xxxviii)    N-[2-(4-cyanophenoxy)ethyl]-N-{2-[7-(pyridin-3-ylmethyl)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl]ethyl}methanesulfonamide;-   (xxxix)    N-[2-(4-cyanophenoxy)ethyl]-N-(2-{7-[(3,5-dimethylisoxazol-4-yl)methyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}ethyl)methanesulfonamide;-   (xl)    N-[2-(4-cyanophenoxy)ethyl]-N-(2-{7-[(2,4-dimethyl-1,3-thiazol-5-yl)methyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}ethyl)methanesulfonamide;-   (xli)    N-[2-(4-cyanophenoxy)ethyl]-N-(2-{7-[(1-methyl-1H-imidazol-2-yl)methyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}ethyl)methanesulfonamide;-   (xlii)    N-benzyl-N-{2-[7-(4-cyanobenzyl)-9-oxa-3,7-diazabicyclo-[3.3.1]non-3-yl]ethyl}methanesulfonamide;-   (xliii)    N-[2-(4-cyanophenoxy)ethyl]-N-{2-[7-(3-phenylpropyl)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl]ethyl}methanesulfonamide;-   (xliv)    N-[2-(4-cyanophenoxy)ethyl]-N-(2-{7-[3-(4-cyanophenyl)propyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}ethyl)methanesulfonamide;-   (xlv)    N-[2-(4-cyanophenoxy)ethyl]-N-(2-{7-[3-(3-methoxyphenyl)propyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}ethyl)methanesulfonamide;-   (xlvi)    N-[2-(4-cyanophenoxy)ethyl]-N-{2-[7-(2,6-dimethylbenzyl)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl]ethyl}methanesulfonamide;-   (xlvii)    N-{2-[7-(4-tert-butylbenzyl)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl]ethyl}-N-[2-(4-cyanophenoxy)ethyl]methanesulfonamide;-   (xlviii)    N-[2-(7-benzyl-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl)ethyl]-N-[2-(4-cyanophenoxy)ethyl]-N′,N′-dimethylurea;-   (xlix)    N-{2-[7-(4-cyanobenzyl)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl]ethyl}-N-[2-(4-cyanophenoxy)ethyl]-N′,N′-dimethylurea;-   (l)    N-[2-(4-cyanophenoxy)ethyl]-N-(2-{7-[2-fluoro-4-(trifluoromethyl)benzyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}ethyl)-N′,N′-dimethylurea;-   (li)    N-[2-(4-cyanophenoxy)ethyl]-N-{2-[7-(4-fluorobenzyl)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl]ethyl}-N′,N′-dimethylurea;-   (lii)    N-[2-(4-cyanophenoxy)ethyl]-N-(2-{7-[4-(difluoromethoxy)-benzyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}ethyl)-N′,N′-dimethylurea;-   (liii)    N-[2-(4-cyanophenoxy)ethyl]-N′,N′-dimethyl-N-{2-[7-(2-phenylethyl)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl]ethyl}urea;-   (liv)    N-[2-(4-cyanophenoxy)ethyl]-N-(2-{7-[2-(4-cyanophenyl)ethyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}ethyl)-N′,N′-dimethylurea;-   (lv)    N-[2-(4-cyanophenoxy)ethyl]-N-(2-{7-[2-(3-fluorophenyl)ethyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}ethyl)-N′,N′-dimethylurea;-   (lvi)    N-[2-(4-cyanophenoxy)ethyl]-N′,N′-dimethyl-N-{2-[7-(3-phenylpropyl)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl]ethyl}urea;-   (lvii)    N-[2-(4-cyanophenoxy)ethyl]-N-{2-[7-(2-phenylethyl)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl]ethyl}methanesulfonamide;-   (lviii)    N-[2-(4-cyanophenoxy)ethyl]-N-(2-{7-[2-(4-cyanophenyl)ethyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}ethyl)methanesulfonamide;-   (lix)    N-[2-(4-cyanophenoxy)ethyl]-N-(2-{7-[2-(4-fluorophenyl)ethyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}ethyl)methanesulfonamide;-   (lx)    N-benzyl-N-(2-{7-[2-(4-cyanophenoxy)ethyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}ethyl)methanesulfonamide;-   (lxi)    N-(2-{7-[2-(4-cyanophenoxy)ethyl]-9-oxa-3,7-diazabicyclo-[3.3.1]non-3-yl}ethyl)-N-(2-phenylethyl)methanesulfonamide;-   (lxii)    N-(2-{7-[3-(4-cyanophenoxy)propyl]-9-oxa-3,7-diazabicyclo-[3.3.1]non-3-yl}ethyl)-N-(2-phenylethyl)methanesulfonamide;-   (lxiii)    N-(2-{7-[2-(4-cyanophenoxy)ethyl]-9-oxa-3,7-diazabicyclo-[3.3.1]non-3-yl}ethyl)-N-(2-phenoxyethyl)methanesulfonamide;-   (lxiv)    N-{2-[7-(4-cyanobenzyl)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl]ethyl}-N-(2-phenoxyethyl)methanesulfonamide;-   (lxv)    N-{2-[7-(4-cyanobenzyl)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl]ethyl}-N-(2-phenylethyl)methanesulfonamide;-   (lxvi)    N-(2-{7-[3-(4-cyanophenoxy)propyl]-9-oxa-3,7-diazabicyclo-[3.3.1]non-3-yl}ethyl)-N-(2-phenoxyethyl)methanesulfonamide;-   (lxvii)    N-benzyl-N-{2-[7-(4-fluorobenzyl)-9-oxa-3,7-diazabicyclo-[3.3.1]non-3-yl]ethyl}methanesulfonamide;-   (lxviii)    N-benzyl-N-{2-[7-(4-chlorobenzyl)-9-oxa-3,7-diazabicyclo-[3.3.1]non-3-yl]ethyl}methanesulfonamide;-   (lxix)    N-benzyl-N-{2-[7-(4-cyanobenzyl)-9-oxa-3,7-diazabicyclo-[3.3.1]non-3-yl]ethyl}benzenesulfonamide;-   (lxx)    N-(4-cyanobenzyl)-N-{2-[7-(4-cyanobenzyl)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl]ethyl}methanesulfonamide;-   (lxxi)    N-(2-cyanobenzyl)-N-{2-[7-(4-cyanobenzyl)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl]ethyl}methanesulfonamide;-   (lxxii)    N-{2-[7-(4-cyanobenzyl)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl]ethyl}-N-(4-fluorobenzyl)methanesulfonamide;-   (lxxiii)    N-{2-[7-(4-cyanobenzyl)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl]ethyl}-N-(3-fluorobenzyl)methanesulfonamide;-   (lxxiv)    N-{2-[7-(4-cyanobenzyl)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl]ethyl}-N-[4-(difluoromethoxy)benzyl]methanesulfonamide;-   (lxxv)    N-(4-chlorobenzyl)-N-{2-[7-(4-cyanobenzyl)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl]ethyl}methanesulfonamide;-   (lxxvi)    N-benzyl-N-{2-[7-(4-cyanobenzyl)-9-oxa-3,7-diazabicyclo-[3.3.1]non-3-yl]ethyl}ethanesulfonamide;-   (lxxvii)    N-benzyl-N-{2-[7-(4-cyanobenzyl)-9-oxa-3,7-diazabicyclo-[3.3.1]non-3-yl]ethyl}-N′-methylurea;-   (lxxviii)    N-benzyl-N-{2-[7-(4-cyanobenzyl)-9-oxa-3,7-diazabicyclo-[3.3.1]non-3-yl]ethyl}-N′,N′-dimethylurea;-   (lxxix)    N-benzyl-N-(2-{7-[2-(4-cyanophenyl)ethyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}ethyl)methanesulfonamide;-   (lxxx)    N-benzyl-N-(2-{7-[2-(2,4-dicyanophenoxy)ethyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}ethyl)methanesulfonamide;-   (lxxxi)    N-benzyl-N-(2-{7-[3-(4-cyanophenoxy)propyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}ethyl)methanesulfonamide;-   (lxxxii)    N-benzyl-N-{2-[7-(4-cyanobenzyl)-9-oxa-3,7-diazabicyclo-[3.3.1]non-3-yl]ethyl}-1,1,1-trifluoromethanesulfonamide;-   (lxxxiii)    N-benzyl-N-{2-[7-(4-cyanobenzyl)-9-oxa-3,7-diazabicyclo-[3.3.1]non-3-yl]ethyl}acetamide;-   (lxxxiv)    N-benzyl-N-{2-[7-(4-cyanobenzyl)-9-oxa-3,7-diazabicyclo-[3.3.1]non-3-yl]ethyl}urea;-   (lxxxv)    N-benzyl-N-{2-[7-(4-cyanobenzyl)-9-oxa-3,7-diazabicyclo-[3.3.1]non-3-yl]ethyl}propane-2-sulfonamide;    and-   (lxxxvi)    N-{2-[7-(4-cyanobenzyl)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl]ethyl}-N-(4-fluorobenzyl)urea;    or a pharmaceutically acceptable derivative thereof.

Preparation

According to the invention there is also provided a process for thepreparation of compounds of formula I which comprises:

(a) reaction of a compound of formula II,

wherein R², R⁴, R⁴¹ to R⁴⁶, A, B and G are as hereinbefore defined, witha compound of formula III,

R¹-L¹  III

wherein L¹ represents a leaving group such as halo, alkanesulfonate,perfluoroalkanesulfonate, arenesulfonate, —OC(O)XR⁷, imidazole or R²³O—(wherein R²³ represents, for example, C₁₋₁₀ alkyl or aryl, which groupsare optionally substituted by one or more halo or nitro groups) and X,R¹ and R⁷ are as hereinbefore defined, for example at between room andreflux temperature in the presence of a suitable base (e.g.triethylamine, potassium carbonate or a bicarbonate, such as sodiumbicarbonate) and an appropriate solvent (e.g. dichloromethane,chloroform, acetonitrile, N,N-dimethylformamide, THF, toluene, water, alower alkyl alcohol (e.g. ethanol) or mixtures thereof);(b) for compounds of formula I in which R¹ represents —C(O)XR⁷ or—C(O)N(R^(8a))R^(5d), reaction of a compound of formula IV,

wherein R², R⁴, R⁴¹ to R⁴⁶, A, B, G and L¹ are as hereinbefore defined,with a compound of formula V,

R²⁴—H  V

wherein R²⁴ represents —XR⁷ or —N(R^(8a))R^(5d) and R^(5d), R⁷, R^(8a)and X are as hereinbefore defined, for example under similar conditionsto those described hereinbefore (process step (a));(c) for compounds in which R¹ represents —C(O)N(H)R^(8a), reaction of acompound of formula II, as hereinbefore defined, with a compound offormula VI,

R^(8a)—N═C═O  VI

wherein R^(8a) is as hereinbefore defined, for example at between 0° C.and reflux temperature in the presence of an appropriate organic solvent(e.g. dichloromethane), or via solid phase synthesis under conditionsknown to those skilled in the art;(d) reaction of a compound of formula VII,

wherein R¹ and R⁴¹ to R⁴⁶ are as hereinbefore defined, with a compoundof formula VIII,

wherein L² represents a leaving group such as halo, alkanesulfonate(e.g. mesylate), perfluoroalkanesulfonate or arenesulfonate (e.g.benzenesulfonate, 2- or 4-nitrobenzenesulfonate or, particularly,toluenesulfonate) and R², R⁴, A, B and G are as hereinbefore defined,for example at elevated temperature (e.g. between 35° C. and refluxtemperature) in the presence of a suitable base (e.g. triethylamine orpotassium carbonate) and an appropriate organic solvent (e.g.acetonitrile, dichloromethane, chloroform, dimethylsulfoxide,N,N-dimethylformamide, a lower alkyl alcohol (e.g. ethanol), isopropylacetate or mixtures thereof);(e) for compounds of formula I in which A represents C₃₋₆ alkylenesubstituted in the 2-position (relative to the oxabispidine N-atom) by—OH or amino, reaction of a compound of formula VII, as hereinbeforedefined, with a compound of formula IX,

or a protected derivative thereof, wherein Y represents O or NH and R²,R⁴, B and G are as hereinbefore defined, for example at elevatedtemperature (e.g. 60° C. to reflux) in the presence of a suitablesolvent (e.g. a lower alkyl alcohol (e.g. IPA), acetonitrile, or amixture of a lower alkyl alcohol and water);(f) for compounds of formula I in which B represents -Z²-O—, reaction ofa compound of formula X,

wherein R¹, R², R⁴¹ to R⁴⁶, A and Z² are as hereinbefore defined, with acompound of formula XI,

wherein R⁴ and G are as hereinbefore defined, for example underMitsunobu-type conditions e.g. at between ambient (e.g. 25° C.) andreflux temperature in the presence of a tertiary phosphine (e.g.tributylphosphine or triphenylphosphine), an azodicarboxylate derivative(e.g. diethylazodicarboxylate or 1,1′-(azodicarbonyl)dipiperidine) andan appropriate organic solvent (e.g. dichloromethane or toluene);(g) for compounds of formula I in which G represents N and B represents-Z²-O—, reaction of a compound of formula X, as hereinbefore defined,with a compound of formula XII,

wherein R⁴ and L² are as hereinbefore defined, for example at between10° C. and reflux temperature in the presence of a suitable base (e.g.sodium hydride) and an appropriate solvent (e.g. N,N-dimethylformamide);(h) for compounds of formula I in which B is as hereinbefore defined,except that it does not represent a direct bond, reaction of a compoundof formula XIII,

wherein R¹, R², R⁴¹ to R⁴⁶ and A are as hereinbefore defined, with acompound of formula XIV,

wherein B^(a) represents B as hereinbefore defined, except that it doesnot represent a direct bond, and R⁴, G, and L² are as hereinbeforedefined, for example at elevated temperature (e.g. between 35° C. andreflux temperature) in the presence of a suitable base (e.g.triethylamine or potassium carbonate) and an appropriate organic solvent(e.g. acetonitrile, dichloromethane, chloroform, dimethylsulfoxide,N,N-dimethylformamide, a lower alkyl alcohol (e.g. ethanol), isopropylacetate or mixtures thereof);(i) reaction of a compound of formula XV,

wherein R¹, R⁴, R⁴¹ to R⁴⁶, A, B and G are as hereinbefore defined, witha compound of formula XVI,

R²-L³  XI

wherein L³ represents a suitable leaving group (such as halo,—OS(O)₂R^(3a), —OC(O)OR^(3b), —OC(O)R^(3c) or —NH₂), and R² is ashereinbefore defined, for example under conditions known to thoseskilled in the art (such as: (1) when R² represents —S(O)₂R^(3a),—C(O)N(R^(3d))(R^(3e)) or S(O)₂N(R^(3f))(R^(3g)) and L³ represents haloor —OS(O)₂R^(3a), reaction at between sub-ambient temperature (e.g. 0 to10° C.) and ambient temperature (e.g. 20 to 30° C.) in the presence of asuitable base (e.g. triethylamine) and an appropriate solvent (e.g.DCM); and (2) when R² represents —C(O)N(R^(3d))(R^(3e)) and L³represents —N(R^(3d))(R^(3e)), reaction at elevated temperature (e.g.110 to 150° C., such as 130° C.));(j) for compounds of formula I in which R² represents —C(O)N(H)R^(3d),reaction of a compound of formula XV, as hereinbefore defined, with acompound of formula XVII

O═C═N—R  XVII

wherein R represents a monovalent metal cation (e.g. an alkali metalcation, such as a potassium ion) or R represents R^(3d) as hereinbeforedefined, except that it does not represent H, for example underconditions known to those skilled in the art (such as when R representsa potassium ion, reaction at ambient temperature (e.g. 15 to 30° C.) inthe presence of a suitable acid (e.g. acetic acid) and an appropriatesolvent (e.g. 1,4-dioxane, water, or a mixture thereof);(k) for compounds of formula I in which R¹ represents C₁₋₁₂ alkylsubstituted by one or more substituents as defined above in respect ofR¹, which substituent(s) is/include a —N(R^(9b))S(O)₂R^(9d) group,reaction of a compound of formula XVII,

wherein R^(1a) represents C₁₋₁₂ alkylene, which group is optionallysubstituted by one or more substituents as defined above in respect ofR¹, and R², R⁴, R^(9b), R⁴¹ to R⁴⁶, A, B and G are as hereinbeforedefined, with a compound of formula XIX,

L²-S(O)₂R^(9d)  XIX

wherein R^(9d) and L² are as hereinbefore defined, for example underconditions that are know to those skilled in the art (e.g. at ambienttemperature (such as from 15 to 30° C.) in the presence of a suitablebase (such as such as triethylamine, potassium carbonate or sodiumhydrogencarbonate) and an appropriate solvent (such as DCM, CHCl₃,acetonitrile, DMF, THF, toluene, or mixtures thereof);(l) for compounds of formula I in which R¹ represents C₁₋₁₂ alkylsubstituted by one or more substituents as defined above in respect ofR¹, which substituent(s) is/include a —S(O)₂N(R^(9b))R^(9c) or—N(R^(9b))S(O)₂R^(9d) group, reaction of a compound of formula II, ashereinbefore defined, with a compound of formula XIXA or XIXB,

L¹-R^(1a)—SO₂—N(R^(9b))R^(9c)  XIXA

L¹-R^(1a)—N(R^(9b))—SO₂—R^(9d)  XIXB

wherein L¹, R^(1a), R^(9b), R^(9c) and R^(9d) are as hereinbeforedefined, for example under conditions that are know to those skilled inthe art (e.g. at ambient temperature to reflux in the presence of asuitable base (such as such as triethylamine, potassium carbonate orsodium hydrogencarbonate) and an appropriate solvent (such as DCM,CHCl₃, acetonitrile, DMF, THF, toluene, or mixtures thereof);(m) for compounds of formula I in which R¹ represents —C(O)XR⁷,—C(O)N(R^(8a))R^(5d) or —S(O)₂R^(9a), reaction of a compound of formulaXX,

wherein R^(1a) represents —C(O)XR⁷, —C(O)N(R^(8a))R^(5d) or —S(O)₂R^(9a)and R^(5d), R⁷, R^(8a), R^(9a), R⁴¹ to R⁴⁶ and L² are as hereinbeforedefined, with a compound of formula XXI,

wherein R², R⁴, A, B and G are as hereinbefore defined, for example atbetween room and reflux temperature in the presence of a suitable base(e.g. sodium hydrogencarbonate or potassium carbonate) and anappropriate organic solvent (e.g. acetonitrile);(n) for compounds of formula I which are oxabispidine-nitrogen N-oxidederivatives, oxidation of the corresponding oxabispidine nitrogen of acorresponding compound of formula I, in the presence of a suitableoxidising agent (e.g. MCPBA), for example at 0° C. in the presence of asuitable organic solvent (e.g. dichloromethane);(o) for compounds of formula I which are C₁₋₄ alkyl quaternary ammoniumsalt derivatives, in which the alkyl group is attached to a oxabispidinenitrogen, reaction, at the oxabispidine nitrogen, of a correspondingcompound of formula I with a compound of formula XXII,

R²⁵-L⁴  XXII

wherein R²⁵ represents C₁₋₄ alkyl and L⁴ is a leaving group such ashalo, alkanesulfonate or arenesulfonate, for example at room temperaturein the presence of an appropriate organic solvent (e.g.N,N-dimethylformamide), followed by purification (using e.g. HPLC) inthe presence of a suitable counter-ion provider (e.g. NH₄OAc);(o) conversion of one R⁴ substituent to another using techniques wellknown to those skilled in the art;(p) introduction of one or more (further) R⁴ substituents to thearomatic ring using techniques well known to those skilled in the art(e.g. chlorination);(q) for compounds of formula I in wherein R¹ represents C₁₋₁₂ alkylene,which group is optionally substituted by one or more substituents asdefined above in respect of R¹, reaction of a compound of formula II

wherein R², R⁴, R⁴¹ to R⁴⁶, A, B and G are as hereinbefore defined, withthe appropriate aldehyde, for example under conditions that are known tothose skilled in the art (e.g. at room temperature, such as from 15 to30° C.) in the presence of a reducing agent (such as sodiumcyanoborohydride, sodium triacetoxyborohydride, or similar compounds)and an appropriate solvent (such as 1,2-dichloroethane, dichloroethane,methanol, ethanol or mixtures thereof);(r) reaction of a compound with formula VII

wherein R¹ and R⁴¹ to R⁴⁶ are as hereinbefore defined, with a compoundof formula XXIII

wherein R², R⁴, B and G are as hereinbefore defined, for example underconditions that are known to those skilled in the art (e.g. at roomtemperature, such as from 15 to 30° C.) in the presence of a reducingagent (such as sodium cyanoborohydride, sodium triacetoxyborohydride, orsimilar hydride donating compounds) and an appropriate solvent (such as1,2-dichloroethane, dichloroethane, methanol, ethanol or mixturesthereof); or(s) deprotection of a protected derivative of a compound of formula I asdefined above.

Compounds of formulae II, IV, VII, VIII, IX, X, XIII, XV, XVIII, XX andXXI may be prepared according to or by analogy with the proceduresdescribed or referred to in WO 01/28992, WO 02/28863, WO 02/28864, WO02/83690 and WO 02/83691, the disclosures of which documents are herebyincorporated by reference.

Compounds of formulae III, V, VI, XI, XII, XIV, XVI, XVII, XIX, XIXA,XIXB, XXII and derivatives thereof, are either commercially available,are known in the literature, or may be obtained either by analogy withthe processes described herein, or by conventional synthetic procedures,in accordance with standard techniques, from readily available startingmaterials using appropriate reagents and reaction conditions.

Substituents on the aryl (e.g. phenyl), and (if appropriate)heterocyclic, group(s) in compounds defined herein may be converted toother claimed substituents using techniques well known to those skilledin the art. For example, hydroxy may be converted to alkoxy, phenyl maybe halogenated to give halophenyl, nitro may be reduced to give amino,halo may be displaced by cyano, etc.

The skilled person will also appreciate that various standardsubstituent or functional group interconversions and transformationswithin certain compounds of formula I will provide other compounds offormulae I. For example, carbonyl may be reduced to hydroxy or alkylene,and hydroxy may be converted to halo.

The compounds of the invention may be isolated from their reactionmixtures using conventional techniques.

It will be appreciated by those skilled in the art that, in the processdescribed above, the functional groups of intermediate compounds may be,or may need to be, protected by protecting groups.

Functional groups which it is desirable to protect include hydroxy,amino and carboxylic acid. Suitable protecting groups for hydroxyinclude trialkylsilyl and diarylalkylsilyl groups (e.g.tert-butyldimethylsilyl, tert-butyldiphenylsilyl or trimethylsilyl),tetrahydropyranyl and alkylcarbonyl groups (e.g. methyl- andethylcarbonyl groups). Suitable protecting groups for amino includebenzyl, sulfonamido (e.g. benzenesulfonamido), tert-butyloxycarbonyl,9-fluorenyl-methoxycarbonyl or benzyloxycarbonyl. Suitable protectinggroups for amidino and guanidino include benzyloxycarbonyl. Suitableprotecting groups for carboxylic acid include C₁₋₆ alkyl or benzylesters.

The protection and deprotection of functional groups may take placebefore or after any of the reaction steps described hereinbefore.Protecting groups may be removed in accordance with techniques which arewell known to those skilled in the art and as described hereinafter.

The use of protecting groups is fully described in “Protective Groups inOrganic Chemistry”, edited by J. W. F. McOmie, Plenum Press (1973), and“Protective Groups in Organic Synthesis”, 3^(rd) edition, T. W. Greene &P. G. M. Wutz, Wiley-Interscience (1999).

Persons skilled in the art will appreciate that, in order to obtaincompounds of the invention in an alternative, and, on some occasions,more convenient, manner, the individual process steps mentioned hereinmay be performed in a different order, and/or the individual reactionsmay be performed at a different stage in the overall route (i.e.substituents may be added to and/or chemical transformations performedupon, different intermediates to those associated hereinbefore with aparticular reaction). This will depend inter alia on factors such as thenature of other functional groups present in a particular substrate, theavailability of key intermediates and the protecting group strategy (ifany) to be adopted. Clearly, the type of chemistry involved willinfluence the choice of reagent that is used in the said syntheticsteps, the need, and type, of protecting groups that are employed, andthe sequence for accomplishing the synthesis.

It will also be appreciated by those skilled in the art that, althoughcertain protected derivatives of compounds of formula I, which may bemade prior to a final deprotection stage, may not possesspharmacological activity as such, they may be administered parenterallyor orally and thereafter metabolised in the body to form compounds ofthe invention which are pharmacologically active. Such derivatives maytherefore be described as “prodrugs”. Moreover, certain compounds offormula I may act as prodrugs of other compounds of formula I.

All prodrugs of compounds of formula I are included within the scope ofthe invention.

Some of the intermediates referred to hereinbefore are novel. Accordingto a further aspect of the invention there is thus provided: (a) acompound of formula II, as hereinbefore defined, or a protectedderivative thereof; (b) a compound of formula IV, or a protectedderivative thereof; (c) a compound of formula VIII, or a protectedderivative thereof; (d) a compound of formula IX, or a protectedderivative thereof; (e) a compound of formula X, or a protectedderivative thereof; (f) a compound of formula XIII, or a protectedderivative thereof; (g) a compound of formula XV, or a protectedderivative thereof, provided that A is interrupted by —S(O)₂N(R^(18a))—or —N(R^(18b))S(O)₂— and/or B represents -Z¹-[C(O)]_(a)C(H)(R^(19a))—,-Z²-[C(O)]_(c)N(R^(19b))—, -Z²-N(R^(18c))S(O)₂— or -Z²-S(O)₂N(R^(18d))—,wherein R^(19a) is other than H and R^(19b) is other than H or C₁₋₆alkyl; (h) a compound of formula XVIII, or a protected derivativethereof; and (i) a compound of formula XXI, or a protected derivativethereof.

Medical and Pharmaceutical Use

Compounds of the invention are useful because they possesspharmacological activity. They are therefore indicated aspharmaceuticals.

Thus, according to a further aspect of the invention there is providedthe compounds of the invention for use as pharmaceuticals.

In particular, the compounds of the invention exhibit myocardialelectrophysiological activity, for example as demonstrated in the testdescribed below.

The compounds of the invention are thus expected to be useful in boththe prophylaxis and the treatment of arrhythmias, and in particularatrial and ventricular arrhythmias.

The compounds of the invention are thus indicated in the treatment orprophylaxis of cardiac diseases, or in indications related to cardiacdiseases, in which arrhythmias are believed to play a major role,including ischaemic heart disease, sudden heart attack, myocardialinfarction, heart failure, cardiac surgery and thromboembolic events.

In the treatment of arrhythmias, compounds of the invention have beenfound to selectively delay cardiac repolarization and increaserefractoriness.

According to a further aspect of the invention, there is provided amethod of treatment of an arrhythmia which method comprisesadministration of a therapeutically effective amount of a compound ofthe invention to a person suffering from, or susceptible to, such acondition.

Pharmaceutical Preparations

The compounds of the invention will normally be administered orally,subcutaneously, intravenously, intraarterially, transdermally,intranasally, by inhalation, or by any other parenteral route, in theform of pharmaceutical preparations comprising the active ingredienteither as a free base or a non-toxic organic or inorganic acid additionsalt, in a pharmaceutically acceptable dosage form. Depending upon thedisorder and patient to be treated, as well as the route ofadministration, the compositions may be administered at varying doses.

The compounds of the invention may also be combined with any other drugsuseful in the treatment of arrhythmias and/or other cardiovasculardisorders. In particular the compounds of the invention may be combinedwith an anti-coagulant.

When used herein, the term “an anticoagulant” includes references to onea substance selected from the group consisting of aspirin, warfarin,enoxaparin, heparin, low molecular weight heparin, cilostazol,clopidogrel, ticlopidine, tirofiban, abciximab, dipyridamole, plasmaprotein fraction, human albumin, low molecular weight dextran,hetastarch, reteplase, alteplase, streptokinase, urokinase, dalteparin,filgrastin, immunoglogulin, ginkolide B, hirudins, foropafant,rocepafant, bivalirudin, dermatan sulfate mediolanum, eptilibatide,tirofiban, thrombomodulin, abcxmab, low molecular weight dermatansulfate-opocrin, eptacog alfa, argatroban, fondaparinux sodium,tifacogin, lepirudin, desirudin, OP2000, roxifiban, parnaparin sodium,human hemoglobin (Hemosol), bovine hemoglobin (Biopure), humanhemoglobin (Northfield), antithrombin III, RSR 13, heparin-oral(Emisphere) transgenic antithrombin III, H37695, enoxaparin sodium,mesoglycan, CTC 111, bivalirudin, and any derivatives and/orcombinations thereof.

Particular anticoagulants that may be mentioned include aspirin andwarfarin.

The term “an anticoagulant” also includes references to thrombininhibitors. Thrombin inhibitors that may be mentioned include lowmolecular weight thrombin inhibitors. The term “low molecular weightthrombin inhibitors” will be understood by those skilled in the art, andincludes references to any composition of matter (e.g. chemicalcompound) that inhibits thrombin to an experimentally determinabledegree (as determined by in vivo and/or in vitro tests), and whichpossesses a molecular weight of below about 2,000, preferably belowabout 1,000.

Preferred low molecular weight thrombin inhibitors include low molecularweight peptide-based, amino acid-based, and/or peptide analogue-based,thrombin inhibitors, as well as derivatives thereof.

The term “low molecular weight peptide-based, amino acid-based, and/orpeptide analogue-based, thrombin inhibitors” will be well understood byone skilled in the art to include references to low molecular weightthrombin inhibitors with one to four peptide linkages, and includesthose described in the review paper by Claesson in Blood Coagul. Fibrin.5, 411 (1994), as well as those disclosed in

U.S. Pat. No. 4,346,078, International Patent Applications WO 93/11152,WO 93/18060, WO 93/05069, WO 94/20467, WO 94/29336, WO 95/35309, WO95/23609, WO 96/03374, WO 96/06832, WO 96/06849, WO 96/25426, WO96/32110, WO 97/01338, WO 97/02284, WO 97/15190, WO 97/30708, WO97/40024, WO 97/46577, WO 98/06740, WO 97/49404, WO 97/11693, WO97/24135, WO 97/47299, WO 98/01422, WO 98/57932, WO 99/29664, WO98/06741, WO 99/37668, WO 99/37611, WO 98/37075, WO 99/00371, WO99/28297, WO 99/29670, WO 99/40072, WO 99/54313, WO 96/31504, WO00/01704 and WO 00/08014; and European Patent Applications 648 780, 468231, 559 046, 641 779, 185 390, 526 877, 542 525, 195 212, 362 002, 364344, 530 167, 293 881, 686 642, 669 317, 601 459 and 623 596, thedisclosures in all of which documents are hereby incorporated byreference.

In the present application, derivatives of thrombin inhibitors includechemical modifications, such as esters, prodrugs and metabolites,whether active or inactive, and pharmaceutically acceptable salts andsolvates, such as hydrates, of any of these, and solvates of any suchsalt.

Preferred low molecular weight peptide-based thrombin inhibitors includethose known collectively as the “gatrans”. Particular gatrans which maybe mentioned include HOOC—CH₂—(R)Cha-Pic-Nag-H (known as inogatran) andHOOC—CH₂—(R)Cgl-Aze-Pab-H (known as melagatran) (see InternationalPatent Application WO 93/11152 and WO 94/29336, respectively, and thelists of abbreviations contained therein).

International Patent Application WO 97/23499 discloses a number ofcompounds which have been found to be useful as prodrugs of thrombininhibitors. Said prodrugs have the general formula

R_(a)OOC—CH₂—(R)Cgl-Aze-Pab-R_(b)

wherein R_(a) represents H, benzyl or C₁₋₁₀ alkyl, R^(b) (which replacesone of the hydrogen atoms in the amidino unit of Pab-H) represents OH,OC(O)R_(c) or C(O)OR_(d), R_(c) represents C₁₋₁₇ alkyl, phenyl or2-naphthyl and R_(d) represents C₁₋₁₂ alkyl, phenyl, C₁₋₃ alkylphenyl,or 2-naphthyl. Preferred compounds includeR_(a)OOC—CH₂—(R)Cgl-Aze-Pab-OH, wherein R_(a) represents benzyl or C₁₋₁₀alkyl, e.g. ethyl or isopropyl, especially EtOOC—CH₂—(R)Cgl-Aze-Pab-OH.The active thrombin inhibitors themselves are disclosed in WO 94/29336.

According to a further aspect of the invention there is thus provided apharmaceutical formulation including a compound of the invention inadmixture with a pharmaceutically acceptable adjuvant, diluent orcarrier.

Suitable daily doses of the compounds of the invention in therapeutictreatment of humans are about 0.005 to 50.0 mg/kg body weight at oraladministration and about 0.005 to 15.0 mg/kg body weight at parenteraladministration. Preferable ranges of daily doses of the compounds of theinvention in therapeutic treatment of humans are about 0.005 to 20.0mg/kg body weight at oral administration and about 0.005 to 5.0 mg/kgbody weight at parenteral administration.

The compounds of the invention have the advantage that they areeffective against cardiac arrhythmias.

Compounds of the invention may also have the advantage that they may bemore efficacious than, be less toxic than, have a broader range ofactivity (including exhibiting any combination of class I, class II,class III and/or class IV activity (especially class I and/or class IVactivity in addition to class III activity)) than, be more potent than,be longer acting than, produce fewer side effects (including a lowerincidence of proarrhythmias such as torsades de pointes) than, be moreeasily absorbed than, or that they may have other useful pharmacologicalproperties over, compounds known in the prior art.

Biological Tests Test A

Primary Electrophysiological Effects In Anaesthetised Guinea Pigs Guineapigs weighing between 500 and 1000 g were used. The animals were housedfor at least one week before the experiment and had free access to foodand tap water during that period.

Anaesthesia was induced by an intraperitoneal injection of pentobarbital(50 to 60 mg/kg) and catheters were introduced into one carotid artery(for blood pressure recording and blood sampling) and into one jugularvein (for drug infusions). Needle electrodes were placed on the limbsfor recording of ECGs (lead II). A thermistor was placed in the rectumand the animal was placed on a heating pad, set to a rectal temperatureof between 37.5 and 38.5° C.

A tracheotomy was performed and the animal was artificially ventilatedwith room air by use of a small animal ventilator, set to keep bloodgases within the normal range for the species. In order to reduceautonomic influences both vagi were cut in the neck, and 0.5 mg/kg ofpropranolol was given intravenously, 15 minutes before the start of theexperiment.

The left ventricular epicardium was exposed by a left-sided thoracotomy,and a custom-designed suction electrode for recording of the monophasicaction potential (MAP) was applied to the left ventricular free wall.The electrode was kept in position as long as an acceptable signal couldbe recorded, otherwise it was moved to a new position. A bipolarelectrode for pacing was clipped to the left atrium. Pacing (1 msduration, twice the diastolic threshold) was performed with acustom-made constant current stimulator. The heart was paced at afrequency just above the spontaneous sinus rate during 30 s every fifthminute throughout the study.

The MAP signal, the blood pressure signal and the lead II ECG werecollected (the sampling frequency was 1000 Hz and each sampling period10 s) on a personal computer during the last 10 s of each 30 s pacingsequence and the last 10 s of the following min of sinus rhythm. Thesignals were processed using a custom-designed computer program(PharmLab v 4.0).

The test procedure consisted of two basal control recordings, 3 minutesapart, during both pacing and sinus rhythm. After the second controlrecording, the first dose of the test substance was infused in a volumeof is 0.2 mL/kg into the jugular vein catheter for 30 seconds. Threeminutes later, pacing was started and a new recording was made. Fiveminutes after the previous dose, the next dose of test substance wasadministered. Six to ten consecutive doses were given during eachexperiment.

Data Analysis

Of the numerous variables measured in this analysis, three were selectedas the most important for comparison and selection of active compounds.The three variables selected were the MAP duration at 75 percentrepolarization during pacing, the atrio-ventricular (AV) conduction time(defined as the interval between the atrial pace pulse and the start ofthe ventricular MAP) during pacing, and the heart rate (defined as theRR interval during sinus rhythm). Systolic and diastolic blood pressurewere measured in order to judge the haemodynamic status of theanaesthetised animal. Further, the ECG was checked for arrhythmiasand/or morphological changes.

The mean of the two control recordings was set to zero and the effectsrecorded after consecutive doses of test substance were expressed aspercentage changes from this value. By plotting these percentage valuesagainst the cumulative dose administered before each recording, it waspossible to construct dose-response curves. In this way, each experimentgenerated three dose-response curves, one for MAP duration, one forAV-conduction time and one for the sinus frequency (RR interval). A meancurve of all experiments performed with a test substance was calculated,and potency values were derived from the mean curve. All dose-responsecurves in these experiments were constructed by linear connection of thedata points obtained. The cumulative dose prolonging the MAP duration by10% from the baseline was used as an index to assess the class IIIelectrophysiological potency of the agent under investigation (D₁₀).

Test B Rb⁺-Efflux Assay for Detection of HERG Channel Blockers

The human ether-a-go-go related gene (HERG) encodes the voltage-gated K⁺channel underlying the cardiac rapid delayed rectifier current I_(Kr).The IC50 value for HERG channel blockade was determined using a highthroughput functional assay based on depolarisation-induced Rb⁺-effluxfrom Chinese hamster ovary cells stably expressing the HERG-channel.

Cells were grown in Ham F12 (Life Technologies 31765-027) supplementedwith 10% FBS and 0.6 mg/mL hygromycin B and were routinely passagedtwice-weekly. For experimental studies, cells were plated at a densityof 15,000 cells/well in Falcon, 384-well tissue culture-treatedblack-walled clear-bottomed plates and were thereafter incubatedovernight at 37° C. in a cell culture incubator.

Following incubating overnight, cell plates were washed and a Rb⁺-Loadbuffer (a physiological buffer containing Rb⁺) was added. Cell plateswere then incubated for 3 hours and were thereafter washed. Followingthis wash, the test compounds were added. The cell plates were thenincubated for another 10 minutes and, following this incubation period,external K⁺ concentration was increased in order to depolarize the cellsand activate HERG channels. After a ten minute exposure period to theincreased K⁺ concentration, supernatants were transferred to newmicroplates for subsequent determination of Rb⁺ content, using AtomicAbsorption Spectrometry analysis.

The basal Rb⁺ efflux (content of Rb⁺ (mg/L) in supernatants of wellsreceiving only wash buffer) was defined as 100% inhibition and thestimulated Rb⁺ efflux (content of Rb⁺ (mg/L) in supernatants of wellsexposed only to increased external potassium concentration) was definedas 0% inhibition.

Compound activity was expressed as:

$100 \times \left\lbrack {1 - \frac{A - B}{C - B}} \right\rbrack$

A: Rb⁺ content in wells receiving test compound+increased external K⁺.B: Basal Rb⁺ efflux.C: Stimulated Rb⁺ efflux.

The invention is illustrated by way of the following examples.

EXAMPLES General Experimental Procedures

Mass spectra were recorded on one of the following instruments:MUX(8)-LCT, ZQ Masspectrometer and Quattro micro, all from WatersMicromass.

LC-MS:

Separation was performed using Agilent 1100 Series Modules or Waters1525 pump on a ACT (Advanced Chromatography Technologies) ACE C8-3×50 mm3 μm with gradient elution.

Samples were injected using Waters 2700 Sample Manager.

Mobile Phases:

Generic gradients were applied from 5% to 95% acetonitrile.

Buffers containing 10 mM ammonium acetate or 5 mM ammonium formate/5 mMformic acid were used.

The mass spectra were recorded with a Waters ZQ2000 or Waters ZMDequipped with an electrospray interface, switching positive and negativeionization mode. UV spectra were collected by a Agilent 1100 PDA orWaters 2996 DAD and the evaporative light scattering (ELS) signal by aSedere Sedex 55 or 75.

Data collection and evaluation were performed using the MassLynxsoftware.

¹H NMR and ¹³C NMR measurements were performed on a BRUKER ACP 300 andVarian 300, 400, 500 and 600 Mercury, Unity plus and Inovaspectrometers, operating at ¹H frequencies of 300, 400, 500 and 600 MHzrespectively and at ¹³C frequencies of 75.4, 100.6, 125.7 and 150.9 MHzrespectively.

Rotamers may or may not be denoted in spectra depending upon ease ofinterpretation of spectra. Unless otherwise stated, chemical shifts aregiven in ppm with the solvent as internal standard.

Synthesis of Intermediates

The following intermediates were not commercially available, and weretherefore prepared by the methods described below.

Preparation A Methanesulfonic acid2-{[3-(4-cyanophenyl)propyl]methanesulfonylamino}ethyl ester (i)3-(4-Cyanophenyl)acrylic acid ethyl ester

To a solution of 4-bromobenzonitrile (50 g, 0.275 mol) and ethylacrylate (35.4 g, 0.412 mol) in dry DMF (250 mL), palladium acetate(0.61 g, 0.0027 mol), tris-o-tolylphosphine (3.34 g, 0.011 mol) andtriethylamine (57.3 mL, 0.412 mol) were added and refluxed at 95-100° C.for 2 h under an argon atmosphere. The reaction was quenched by addingwater (250 mL) and extracted with ether (3×250 mL). The combined extractwas washed with 1.5 N HCl (250 mL), water and brine and dried oversodium sulfate (anhydrous). Solvent evaporation under reduced pressureand purification by column chromatography over neutral alumina, usingethyl acetate in petroleum ether as eluent, yielded 55 g (90%) of thesub-title compound as an off-white solid.

(ii) 3-(4-Cyanophenyl)propionic acid ethyl ester

Pd/C (5 g, 10%) was added to a solution of 3-(4-cyanophenyl)acrylic acidethyl ester (50 g, 0.25 mol; see step (i) above) in dry ethyl acetate(500 mL) under a nitrogen atmosphere, followed by triethylamine (50.3 g,0.5 mol) and formic acid (57.2 g, 1.24 mol). The mixture was refluxedovernight under a nitrogen atmosphere. After the completion of thereaction (monitored by TLC), the mixture was filtered and the filtratethen washed with water, 5% NaHCO₃ solution and brine, before being driedover sodium sulfate. Solvent evaporation under reduced pressure yielded50 g (99%) of the sub-title compound as a pale yellow oil.

(iii) 4-(3-Hydroxypropyl)benzonitrile

To a solution of LiBH₄ (14 g, 0.65 mol) in dry ether (400 mL) was added3-(4-cyanophenyl)propionic acid ethyl ester (50 g, 0.249 mol; see step(ii) above), followed by methanol (27 mL) dropwise. The reaction mixturewas refluxed for 3 h. After completion (monitored by TLC), the reactionwas quenched by adding cold, saturated ammonium chloride solution (100mL), followed by water (300 mL). The layers were then separated. Theaqueous layer was extracted with ether (2×100 mL) and the combinedorganic layers were washed with brine. After drying over anhydroussodium sulfate, the organic layer was concentrated to give the crudeproduct. This crude product was purified by column chromatography oversilica gel, using ethyl acetate in petroleum ether as eluent. Thisyielded 16.5 g (42%) of the sub-title compound as a pale yellow liquid.

(iv) 4-(3-Bromopropyl)benzonitrile

To a solution of 4-(3-hydroxypropyl)benzonitrile (13 g, 0.081 mol; seestep (iii) above) and triphenylphosphine (42.3 g, 0.16 mol) in DCM (150mL) was added, dropwise at 0-5° C., a solution of CBr₄ (53.5 g, 0.16mol) in DCM (100 mL). The resulting mixture was stirred at roomtemperature overnight. The reaction mixture was concentrated and theproduct was purified by column chromatography over silica gel, usingpetroleum ether in ethyl acetate as eluent, to yield 12.5 g (69%) of thesub-title compound as a yellow liquid.

(v) 4-[3-(2-Hydroxyethylamino)propyl]benzonitrile

To a solution 4-(3-bromopropyl)benzonitrile (8 g, 0.0357 mol; see step(iv) above) in dry acetonitrile (150 mL) were added anhydrous K₂CO₃ (7.4g, 0.0535 mol) and ethanolamine (10.9 g, 0.179 mol). The resultingreaction mixture was then stirred overnight at room temperature, afterwhich it was filtered and concentrated. The crude product thus obtainedwas purified by column chromatography over silica gel, using methanol inchloroform as eluent, to yield 4.2 g (57.5%) of the sub-title compoundas a pale yellow solid.

(vi) Methanesulfonic acid2-{[3-(4-cyanophenyl)propyl]methanesulfonyl-amino}ethyl ester

To a solution of 4-[3-(2-hydroxyethylamino)propyl]benzonitrile (4 g,0.0196 mol; see step (v) above) in dry DCM (80 mL) were added, at 0-5°C., triethylamine (5.9 g, 0.0588 mol) and mesyl chloride (5.6 g, 0.049mol). The resulting mixture was then stirred at room temperature for 30min, after which the reaction was quenched by addition of water (50 mL).The resulting aqueous layer was extracted with DCM (2×50 mL) and thecombined organic layers were washed with brine. Solvent was removedunder reduced pressure and the crude product was recrystallised frommethanol to yield 4.2 g (62%) of the title compound as a white solid.

Preparation BN-[3-(4-Cyanophenyl)propyl]-N-[2-(9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl)ethyl]methanesulfonamide,hydrochloride salt (i)7-(2-{[3-(4-Cyanophenyl)propyl]methanesulfonylamino}ethyl)-9-oxa-3,7-diazabicyclo[3.3.1]nonane-3-carboxylicacid tert-butyl ester

A mixture of 9-oxa-3,7-diaza-bicyclo[3.3.1]nonane-3-carboxylic acidtert-butyl ester (2.35 g, 0.01 mol; see WO 01/28992), methanesulfonicacid 2-{[3-(4-cyanophenyl)propyl]methanesulfonylamino}ethyl ester (3.7g, 0.01 mol; see Preparation A above) and anhydrous K₂CO₃ (2.1 g, 0.015mol) in dry acetonitrile (70 mL) was stirred under nitrogen atmosphereat 55-60° C. for 3 days. After filtration and concentration, the crudeproduct was purified by column chromatography (silica gel: 60-120 mesh,eluent: petroleum ether-ethyl acetate, 50:50). Yield: 3.25 g (66%).

(ii)N-[3-(4-Cyanophenyl)propyl]-N-[2-(9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl)ethyl]methanesulfonamidehydrochloride salt

7-(2-{[3-(4-cyanophenyl)propyl]methanesulfonylamino}ethyl)-9-oxa-3,7-diazabicyclo[3.3.1]nonane-3-carboxylicacid tert-butyl ester (3.8 g, 0.0095 mol; see step (i) above) was addedto a saturated solution of HCl_((g)) in ethyl acetate (50 mL) and theresultant mixture was then stirred overnight. On completion of thereaction (as determined by TLC), ethyl acetate was decanted and theproduct was dried under high vacuum to give the title compound. Yield:1.5 g (54%).

Preparation CN-(2-Bromoethyl)-N-[2-(4-cyanophenoxy)ethyl]methanesulfonamide (i)4-(2-Bromoethoxy)benzonitrile

Anhydrous potassium carbonate (233 g, 1.68 mol) was added to a solutionof 4-hydroxybezonitrile (100 g, 0.84 mol) in DMF (700 mL), and theresultant mixture was stirred for 1 h under a N₂ atmosphere.1,2-Dibromoethane (362 mL, 4.2 mol) was added slowly to the reactionmixture, which was then stirred at 55-60° C. overnight. The reactionmixture was diluted with water and extracted with ethyl acetate (3×750mL). The combined organic layer was washed with water and thenconcentrated. The crude product was purified by column chromatography(silica gel: 60-120 mesh, eluent: petroleum ether-ethyl acetate, 90:10).Yield: 60 g (32%).

(ii) 4-[2-(2-Hydroxyethylamino)ethoxy]benzonitrile

4-(2-Bromoethoxy)benzonitrile (30 g, 0.133 mol; see step (i) above) andethanolamine (48 mL, 0.78 mol) were mixed and refluxed, under a nitrogenatmosphere, at about 120° C. for 3 h. The reaction was quenched byaddition of a sodium hydroxide solution to the mixture. The sub-titlecompound was extracted using DCM (2×250 μL), which was dried overanhydrous sodium sulfate and then concentrated. Yield: 13.1 g (48%).

(iii) Methanesulfonic acid2-{[2-(4-cyanophenoxy)ethyl]methanesulfonyl-amino}ethyl ester

To a solution of 4-[2-(2-hydroxyethylamino)ethoxy]benzonitrile (14 g,0.068 mol; see step (ii) above) in dry DCM (200 mL) was addedtriethylamine (28.4 mL, 0.2 mol), followed by methanesulfonyl chloride(13 mL, 0.17 mol) at 0-5° C. The reaction mixture was stirred at roomtemperature for 1 h. After completion of the reaction (by TLC), water(250 mL) was added and the organic layer was separated. The aqueouslayer was extracted with DCM (2×100 mL) and the combined organic layerswere washed with water. After concentration, the crude product wasfurther purified by column chromatography (silica gel: 60-120 mesh,eluent: chloroform-methanol, 98.5:1.5). Yield: 18.2 g (74%).

(iv) N-(2-Bromoethyl)-N-[2-(4-cyanophenoxy)ethyl]methanesulfonamide

To a solution of methanesulfonic acid2-{[2-(4-cyanophenoxy)ethyl]-methanesulfonylamino}ethyl ester (10 g,0.028 mol; see step (iii) above) in dry acetone (100 mL), was addedlithium bromide (4.8 g, 0.055 mol). The reaction mixture was addedrefluxed overnight under a nitrogen atmosphere, before being filteredand concentrated to give the title compound. Yield: 10 g (97%).

Preparation D Toluene-4-sulfonic acid2-{1-[2-(4-cyanophenoxy)ethyl]ureido}ethyl ester (i)N-[2-(4-Cyanophenoxy)ethyl]-N-(2-hydroxyethyl)urea

To a solution of 4-[2-(2-hydroxyethylamino)ethoxy]benzonitrile (5 g,0.0242 mol; see Preparation C(ii) above) in dioxane (65 mL) and water(65 mL) was added, at rt, potassium cyanate (4.92 g, 0.0606 mol),followed by acetic acid (4.36 g, 0.0726 mol). The reaction mixture wasthen stirred at rt overnight, before being concentrated under reducedpressure. The resulting residue was partitioned between water anddichloromethane. The organic layer was separated, washed with water andbrine, dried over sodium sulfate and then concentrated. The crudeproduct was further purified by column chromatography. Yield: 3.5 g.

(ii) Toluene-4-sulfonic acid 2-{1-[2-(4-cyanophenoxy)ethyl]ureido}ethylester

To a solution of intermediate1-[2-(4-cyanophenoxy)ethyl]-1-(2-hydroxyethyl)urea (4.7 g, 0.0188 mol;see step (i) above) in dry THF (150 mL) was added n-butyllithium (18.89mL, 1.1 M) at −78° C. The reaction mixture was stirred at −78° C. for 1h, after which a solution of freshly crystallised p-toluenesulfonylchloride (4.3 g, 0.023 mol) in THF (50 mL) was added dropwise. Thereaction mixture was then stirred at −78° C. for a further 30 min,before being warmed to −30° C., and stirred for 2 h more. The reactionmixture was quenched with water and extracted with ethyl acetate. Theorganic layer was washed with brine, dried over Na₂SO₄, concentrated andthe residue was recrystallised in ethyl acetate/hexane to yield thetitle compound as an off-white solid. Yield: 3.5 g.

Preparation EN-[2-(4-Cyanophenoxy)ethyl]-N-[2-(9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl)ethyl]urea(i)7-(2-{1-[2-(4-Cyanophenoxy)ethyl]ureido}ethyl)-9-oxa-3,7-diazabicyclo-[3.3.1]nonane-3-carboxylicacid tert-butyl ester

A mixture of toluene-4-sulfonic acid2-{1-[2-(4-cyanophenoxy)ethyl]-ureido}ethyl ester (15 g, 0.0372 mol, 1.0eq.; see Preparation D above),9-oxa-3,7-diaza-bicyclo[3.3.1]nonane-3-carboxylic acid tert-butyl ester(8.525 g, 0.0372 mol, 1.0 eq.; see WO 01/28992), fused K₂CO₃ (7.7 g,0.0558 mol, 1.5 eq.) and lithium bromide (9.6 g, 0.1116 mol, 3.0 eq.) indry acetonitrile (350 mL) was heated to 40° C. under N₂ for 4 days. Thereaction was cooled to rt, filtered and the filtrate was concentratedunder reduced pressure. The resulting residue was purified by columnchromatography over silica gel, using 3% methanol and DCM as eluent, toyield the sub-title compound as a white solid. Yield: 7 g, 40.9%.

(ii)N-[2-(4-Cyanophenoxy)ethyl]-N-[2-(9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl)ethyl]urea

7-(2-{1-[2-(4-Cyanophenoxy)ethyl]ureido}ethyl)-9-oxa-3,7-diazabicyclo-[3.3.1]nonane-3-carboxylicacid tert-butyl ester (6.44 g; see step (i) above) was added to asolution of HCl-saturated, dry dioxane (300 mL) at 0° C. The reactionwas then stirred at rt for 1 hr. The resulting precipitate was filteredunder N₂, washed with dry ether and then dried under vacuum to providethe title compound. Yield: 6 g.

Preparation F Toluene-4-sulfonic acid2-{1-[3-(4-cyanophenyl)propyl]ureido}ethyl ester (i)1-[3-(4-Cyanophenyl)propyl]-1-(2-hydroxyethyl)urea

4-[3-(2-Hydroxyethylamino)propyl]benzonitrile (6.7 g, 0.0328 mol; seePreparation A(v) above) and urea (2 g, 0.0328 mol) were mixed and heatedat 130° C. for 2 h. The reaction mixture was cooled to room temperatureand water was added. The resulting solid was filtered and dried to give5.9 g (72%) of the sub-title compound as a white solid.

(ii) Toluene-4-sulfonic acid 2-{1-[3-(4-cyanophenyl)propyl]ureido}ethylester

1-[3-(4-Cyanophenyl)propyl]-1-(2-hydroxyethyl)urea (5.9 g, 0.0238 mol;see step (i) above) was taken in dry pyridine (20 mL). Freshly preparedp-toluenesulfonyl chloride (4.9 g, 0.02627 mol) was then addedportion-wise at 0° C. The reaction mixture was stirred at 0° C. for 3 h,after which ethyl acetate was added (to remove pyridine from product)and the resulting solid was filtered. The product was then purified bycolumn chromatography, using methanol in dichloromethane as the eluent,followed by crystallisation from isopropanol. This yielded 2.7 g (62%)of the title compound as a colourless, crystalline solid.

¹H NMR (300 MHz; CD₃OD) δ 7.76-7.70 (m, 4H), 7.45 (d, 2H), 7.27 (d, 2H),4.75 (t, 2H), 3.95 (t, 2H), 3.52 (t, 2H), 2.83 (t, 2H), 2.41 (s, 3H),2.0 (m, 2H);

¹³C NMR (75.5 MHz, CD₃OD) δ 163.46, 148.78, 144.13, 142.18, 133.91,131.06, 130.34, 127.41, 120.34, 111.47, 70.52, 48.65, 46.13, 34.05,29.20, 21.81.

Preparation G1-[2-(4-Cyanophenoxy)ethyl]-3,3-dimethyl-1-(2-oxoethyl)urea (i)1-[2-(4-Cyanophenoxy)ethyl]-1-(2-hydroxyethyl)-3,3-dimethylurea

4-{2-[(2-Hydroxyethyl)amino]ethoxy}benzonitrile (5 g, 0.0242 mol; seePreparation C, step (ii) above) was taken in dry dichloromethane (50 mL)and cooled to 0° C. Triethylamine (4 mL, 0.03 mol), followed byN,N-dimethylcarbamoyl chloride (3.9 g, 0.03 mol), was added, and thereaction mixture was stirred at room temperature overnight. The reactionmixture was diluted with water and extracted with dichloromethane. Theorganic layer was washed with water and brine and dried over sodiumsulfate. The solvent was evaporated under reduced pressure. Purificationby column chromatography using dichloromethane in methanol yielded 6 gof the sub-title compound as pale yellow liquid.

(ii) 1-[2-(4-Cyanophenoxy)ethyl]-3,3-dimethyl-1-(2-oxoethyl)urea

Oxalyl chloride (6.3 g, 0.0497 mol) was added dropwise to a stirredsolution of DMSO (7.6 g, 0.094 mol) and dichloromethane (100 mL) at −78°C. After stirring for 15 min at the same temperature,1-[2-(4-cyanophenoxy)ethyl]-1-(2-hydroxyethyl)-3,3-dimethylurea (6 g,0.0325 mol; see step (i) above) in dichloromethane was added andstirring continued for 3 h under a nitrogen atmosphere. Triethylamine(16.4 mL, 0.1625 mol) was added dropwise and the reaction mixture wasthen warmed slowly to −30° C. The reaction mixture was quenched with anaqueous solution of citric acid, and the resulting mixture extractedwith dichloromethane. The organic layer was washed with water and brineand dried over sodium sulfate. Solvent evaporation under reducedpressure yielded 4.5 g of the crude title compound, which was usedwithout further purification.

Preparation H1-[2-(4-Cyanophenoxy)ethyl]-3,3-dimethyl-1-[2-(9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl)ethyl]urea

7-(2-{1-[2-(4-Cyanophenoxy)ethyl]-3,3-dimethylureido}ethyl)-9-oxa-3,7-diazabicyclo[3.3.1]nonane-3-carboxylicacid tert-butyl ester (6.5 g; see Example 5 below) was taken in HCl indioxane (50 mL) and stirred for 30 min. The reaction mixture wasdecanted and the solid was taken in a biphasic mixture ofdichloromethane and aqueous NaHCO₃. The organic layer was separated,washed with water, dried over sodium sulfate and concentrated.Purification by column chromatography yielded 1.3 g of the titlecompound as pale yellow solid.

Preparation I Toluene-4-sulfonic acid2-{1-[2-(4-cyanophenoxy)ethyl]-3-methylureido}-ethyl ester (i)1-[2-(4-Cyanophenoxy)ethyl]-1-(2-hydroxyethyl)-3-methylurea

4-[2-(2-Hydroxyethylamino)ethoxy]benzonitrile (1 g, 0.009 mol; seePreparation C, step (ii) above) and N,N′-dimethylurea (0.43 g, 0.0049mol) were heated with stirring at 130° C. for 4 h. The reaction wasdirectly purified by column chromatography to yield 0.7 g of thesub-title product as an off white solid.

(ii) Toluene-4-sulfonic acid2-{1-[2-(4-cyanophenoxy)ethyl]-3-methylureido}ethyl ester

To a well-stirred solution of1-[2-(4-cyanophenoxy)ethyl]-1-(2-hydroxyethyl)-3-methylurea (6.6 g,0.0257 mol; see step (i) above) in dry THF (70 mL) was added n-BuLi(2.85 N, 1.766 g, 0.0276 mol) at −78° C., dropwise under a nitrogenatmosphere. After stirring at the same temperature for 45 min,p-toluenesulfonyl chloride (5.25 g, 0.0276 mol) in dry THF was added(drop by drop) and the reaction mixture was then stirred at −40° C. for2 h. The reaction was quenched with 50 mL water and warmed to roomtemperature. The product was extracted with ethyl acetate, washed withbrine solution and dried over sodium sulfate. Solvent evaporation underreduced pressure, followed by column chromatography over silica gel(using 15-25% methanol in chloroform) yielded 1.36 g of the titlecompound as a brown gummy liquid.

Preparation J1-[2-(4-Cyanophenoxy)ethyl]-3-methyl-1-[2-(9-oxa-3,7-diazabicyclo[3.3.1]-non-3-yl)ethyl]urea,hydrogen chloride salt

7-(2-{1-[2-(4-Cyanophenoxy)ethyl]-3-methylureido}ethyl)-9-oxa-3,7-diazabicyclo[3.3.1]nonane-3-carboxylicacid tert-butyl ester (920 mg; see Example 6 below) was dissolved in 10mL of dry dioxane, to which was added 10 mL of dioxane saturated withHCl. The reaction mixture was stirred at room temperature for 1 h. Thesolid that formed was filtered, washed with dry diethyl ether and thendried under vacuum to yield 400 mg of the title compound as a yellowsolid.

Preparation K1-[3-(4-Cyanophenyl)propyl]-3,3-dimethyl-1-(2-oxoethyl)urea (i)4-[3-(2-Hydroxyethylamino)propyl]benzonitrile

4-(3-Bromopropyl)benzonitrile (20 g, 0.089 mol) in acetonitrile wasadded to a vigorously stirred mixture of ethanolamine (27.2 g, 0.447mol) and potassium carbonate (18.5 g, 0.133 mol) in 300 mL of dryacetonitrile. Stirring was then continued at room temperature overnightunder a nitrogen atmosphere. The reaction mixture was filtered andconcentrated under reduced pressure. The crude product thereby obtainedwas purified by column chromatography (using methanol in chloroform) toyield 15 g of the sub-title compound.

(ii) 1-[3-(4-Cyanophenyl)propyl]-1-(2-hydroxyethyl)-3,3-dimethylurea

N,N-Dimethylcarbamoyl chloride (3.9 g, 0.0368 mol) was added to amixture of 4-[3-(2-hydroxyethylamino)propyl]benzonitrile (5 g, 0.025mol; see step (i) above) and triethylamine (3.7 g, 0.368 mol) indichloromethane (100 mL) at 0° C. Stirring was then continued at roomtemperature overnight. The reaction mixture was diluted with water andextracted with dichloromethane. The organic layer was washed with waterand brine and dried over sodium sulfate. Solvent evaporation underreduced pressure, followed by purification by column chromatography(using 4% methanol in dichloromethane) yielded 7 g of the sub-titlecompound as a pale yellow, gummy liquid.

(iii) 1-[3-(4-Cyanophenyl)propyl]-3,3-dimethyl-1-(2-oxoethyl)urea

Oxalyl chloride (4.84 g, 0.038 mol) was added dropwise to a stirredsolution of DMSO (5.9 g, 0.0763 mol) and dichloromethane (100 mL) at−78° C. After 15 min at the same temperature,1-[3-(4-cyanophenyl)propyl]-1-(2-hydroxyethyl)-3,3-dimethylurea (7 g,0.0254 mol) in dichloromethane was added and stirring continued for 3 hunder a nitrogen atmosphere. Triethylamine (12.8 g, 0.127 mol) was added(dropwise), and the reaction mixture was then warmed slowly to −30° C.The reaction mixture was quenched with 10% citric acid (aq.) andextracted with dichloromethane. The organic layer was washed with waterand brine, dried over sodium sulfate and concentrated to yield 6.5 g ofthe crude title compound, which was used without further purification.

Preparation L1-[3-(4-Cyanophenyl)propyl]-3,3-dimethyl-1-[2-(9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl)ethyl]urea,hydrogen chloride salt

7-(2-{1-[3-(4-Cyanophenyl)propyl]-3,3-dimethylureido}ethyl)-9-oxa-3,7-diazabicyclo[3.3.1]nonane-3-carboxylicacid tert-butyl ester (7.5 g; see Example 7 below) was taken in dioxane(20 mL, saturated with HCl gas) and stirred for 2 h. The organic layerwas decanted and the residue was washed with dry diethyl ether and driedunder vacuum to yield 3 g the title compound as a pale yellow solid.

Preparation MN-{2-[7-(4-Cyanobenzyl)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl]ethyl}-methanesulfonamide(i) 7-(4-Cyanobenzyl)-9-oxa-3,7-diazabicyclo[3.3.1]nonane-3-carboxylicacid tert-butyl ester

4-Cyanobenzyl bromide (2 g, 0.01 mol),9-oxa-3,7-diazabicyclo[3.3.1]nonane-3-carboxylic acid tert-butyl ester(2.33 g, 0.01 mol; see WO 01/28992) and potassium carbonate (3.52 g,0.026 mol) were taken in dry acetonitrile (25 mL) and stirred at 60° C.overnight under a nitrogen atmosphere. The reaction mixture was cooledto rt, filtered and the filtrate concentrated under reduced pressure.The residue obtained thereby was purified by column chromatography(using 5% ethyl acetate in petroleum ether) to yield 2.6 g of thesub-title compound as a white solid.

(ii) 4-(9-Oxa-3,7-diazabicyclo[3.3.1]non-3-ylmethyl)benzonitrile,hydrogen chloride salt

7-(4-Cyanobenzyl)-9-oxa-3,7-diazabicyclo[3.3.1]nonane-3-carboxylic acidtert-butyl ester (2.2 g) was taken in dioxane (25 mL, saturated with HClgas) and the reaction mixture stirred at room temperature for 3 h. Thedioxane was decanted off the solid product, which was then washed withdiethyl ether and dried under vacuum to yield 1.82 g of the sub-titlecompound as a white solid.

(iii) N-(2-Bromoethyl)methanesulfonamide

A suspension of 2-bromoethylamine hydrobromide salt (15 g, 0.0724 mol)in dichloromethane (220 mL) was treated with triethylamine (18.31 g,0.181 mol) for 30 min. Into the resulting mixture was added, dropwise at0° C., methanesulfonyl chloride (9.11 g, 0.0796 mol). The reactionmixture was then stirred at room temperature for 3 h before beingquenched with water. The organic layer was washed with water and thenbrine before being dried over sodium sulfate. Solvent evaporation underreduced pressure followed by column chromatography over silica gel(using 2% ethyl acetate in petroleum ether as eluent) gave 4.5 g of thesub-title compound as a pale yellow oil.

(iv)N-{2-[7-(4-Cyanobenzyl)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl]-ethyl}methanesulfonamide

4-(9-Oxa-3,7-diazabicyclo[3.3.1]non-3-ylmethyl)benzonitrile, hydrogenchloride salt (1 g, 3.1 mmol; see step (ii) above),N-(2-bromoethyl)methanesulfonamide (0.75 g, 3.72 mmol; see step (iii)above) and potassium carbonate (1.07 g, 7.75 mmol) were taken in dryacetonitrile (20 mL) and stirred for 15 min at rt under a nitrogenatmosphere. The reaction mixture was concentrated under reduced pressureand the residue obtained thereby was partitioned between water anddichloromethane. The organic layer washed with water followed by brineand was then dried over sodium sulfate. Evaporation of the solventfollowed by vacuum drying of the residue gave 0.9 g of the titlecompound as a brown solid.

Preparation NN-Benzyl-N-[2-(9-oxa-3,7-diaza-bicyclo[3.3.1]non-3-yl)-ethyl]-methanesulfonamidehydrochloride (i) N-benzyl ethanolamine

A mixture of benzyl bromide (15 g, 0.0872 mol) and ethanol amine (26.5g, 0.436 mol) was stirred at 120° C. for 3 h. The reaction mixture wasdiluted with brine and extracted with dichloromethane. The organic layerwas washed with water and brine and dried over sodium sulfate. Solventevaporated under reduced pressure and the residue was purified by columnchromatography over silica gel using 4% methanol in dichloromethane aseluent to give N-benzyl ethanolamine (12 g) as a liquid.

(ii) Methanesulfonic acid 2-(benzyl-methanesulfonyl-amino)-ethyl ester

Methanesulfonyl chloride (18.9 g, 0.1655 mol) was added dropwise at 0°C. to a solution of N-benzyl ethanolamine (10 g, 0.0662 mol, from step(i) above) and triethylamine (27.6 ml, 0.1987 mol) in dichloromethane(100 ml). The reaction mixture was stirred at RT for 3 h under nitrogenatmosphere and partitioned between water and dichloromethane. Theorganic layer was separated, washed with water and brine and dried oversodium sulfate. The solvent was evaporated under reduced pressure andthe residue was purified by column chromatography over silica gel using3% methanol in dichloromethane, as eluent to give the sub-title compound(12 g) as a solid.

(iii)7-[2-(Benzyl-methanesulfonyl-amino)-ethyl]-9-oxa-3,7-diazabicyclo[3.3.1]nonane-3-carboxylicacid tert-butyl ester

A suspension of methanesulfonic acid2-(benzyl-methanesulfonyl-amino)-ethyl ester (4 g, 0.0130 mol; from step(ii) above), 9-oxa-3,7-diazabicyclo[3.3.1]nonane-3-carboxylic acidtert-butyl ester (3 g, 0.013 mol; see WO 01/28992)), dry K₂CO₃ (3.6 g,0.026 mol) and lithium bromide (2.2 g, 0.026 mol) in dry acetonitrile(50 ml) was stirred at 60° C. overnight under N₂. The reaction mixturewas filtered and filtrate was concentrated under reduced pressure. Theresidue was purified by column chromatography over silica gel using 4%methanol in dichloromethane as eluent to yield (5 g) of the sub-titlecompound as a solid.

(iv)N-Benzyl-N-[2-(9-oxa-3,7-diaza-bicyclo[3.3.1]non-3-yl)-ethyl]-methanesulfonamidehydrochloride

7-[2-(Benzyl-methanesulfonyl-amino)-ethyl]-9-oxa-3,7-diazabicyclo[3.3.1]nonane-3-carboxylicacid tert-butyl ester (5 g, 0.011 mol, from step (iii) above) was takenin 20 ml of dioxane (saturated with HCl gas) and stirred for 30 min atroom temperature. The precipitated solid was filtered, washed with dryether and dried under vacuum to yield (3 g) of the title compound as anoff white solid.

Preparation O Methanesulfonic acid2-(methanesulfonyl-phenethyl-amino)-ethyl ester (i)2-Phenethylamino-ethanol

A mixture of ethanolamine (10 g, 0.162 mol) and 1-phenylethyl bromide (5g, 0.027 mol) was stirred at 120° C. for 3 h. The reaction mixture waspartitioned between water and dichloromethane. Organic layer was washedwith water and brine, dried over sodium sulfate and concentrated. Theresidue was purified by column chromatography over silica gel using 3%methanol in dichloromethane to afford (2.5 g) of desired product as asolid.

(ii) Methanesulfonic acid 2-(methanesulfonyl-phenethyl-amino)-ethylester

Methanesulfonyl chloride (4.3 g, 0.037 mol) was added dropwise at 0° C.to a well stirred solution of 2-phenethylamino-ethanol (2.5 g, 0.015mol, from step (i) above) and triethylamine (4.6 g, 0.045 mol) in drydichloromethane (50 ml). The reaction mixture was stirred at roomtemperature for 3 h and quenched with water. The reaction mixture wasextracted with dichloromethane. The organic layer was washed with waterand brine, dried over sodium sulfate and concentrated. The residue waspurified by column chromatography over silica gel using 3% methanol indichloromethane as eluent to yield (3 g) of compound as a solid.

Preparation P Methanesulfonic acid2-[methanesulfonyl-(2-phenoxy-ethyl)-amino]-ethyl ester (i)(2-Bromo-ethoxy)-benzene

A suspension of phenol (5 g, 0.053 mol), 1,2-dibromethane (60 g, 0.319mol) and K₂CO₃ (22 g, 0.16 mol) in dry acetonitrile (100 ml) was stirredat 60° C. overnight under nitrogen atmosphere. The reaction mixture wasfiltered and the solvent concentrated under reduced pressure. Theresidue was purified by column chromatography over silica gel using 10%ethyl acetate in petroleum ether as eluent to yield (10 g) of thesub-title compound as a solid.

(ii) 2-(2-Phenoxy-ethylamino)-ethanol

A mixture of ethanolamine (18.2 g, 0.298 mol) and(2-Bromoethoxy)-benzene (10 g, 0.0497 mol, from step (i) above) wasstirred at 120° C. for 3 h. The reaction mixture was partitioned betweenwater and dichloromethane. Organic layer was washed with water andbrine, dried over sodium sulfate and concentrated. Residue was purifiedby column chromatography over silica gel using 4% methanol indichloromethane to afford (3.8 g) of the sub-title compound as a solid.

(iii) Methanesulfonic acid2-[methanesulfonyl-(2-phenoxy-ethyl)-amino]-ethyl ester

Methanesulfonyl chloride (5.5 g, 0.058 mol) was added dropwise by at 0°C. to a well stirred solution of 2-(2-phenoxy-ethylamino)-ethanol (3.5g, 0.0193 mol, from step (ii) above) and triethylamine (5.85 g, 0.058mol) in dry dichloromethane (50 ml). The reaction mixture was stirred atroom temperature for 3 h and quenched with water. The compound wasextracted with dichloromethane. The organic layer was washed with waterand brine, dried over sodium sulfate and concentrated. The residue waspurified by column chromatography over silica gel using 2% methanol indichloromethane as eluent to yield (4 g) of the title compound as ayellow solid.

Preparation Q Trifluoro-methanesulfonic acid2-(benzyl-trifluoromethanesulfonyl-amino)-ethyl ester

(i): Triflic anhydride (11.18 g, 6.5 ml, 39 mmol) dissolved in 90 ml ofDCM was added drop by drop to a well stirred solution of N-benzylethanol amine (2 g, 13.2 mmol) and diisopropylethyl amine (5.1 g, 6.9ml, 39.7 mmol) in dichloromethane (160 ml) at 0° C. and stirred at roomtemperature for 1 h under nitrogen atmosphere. The reaction mixture wasquenched with water and extracted with dichloromethane. Organic layerwas washed with water and dried under sodium sulfate. Solventevaporation under reduced pressure afforded 500 mg of the title compoundas a an oil

Preparation R Toluene-4-sulfonic acid 2-(1-benzyl-3-methyl-ureido)-ethylester (i) 1-Benzyl-1-(2-hydroxy-ethyl)-3-methyl-urea

A mixture of N-benzyl ethanolamine (3 g, 0.0198 mol) and N,N′-dimethylurea was stirred at 130° C. overnight. The reaction mixture was cooledto RT and the crude product was purified by column chromatography oversilica gel using 3% methanol in dichloromethane as eluent to yield 3.5 gof the sub-title compound as a liquid.

(ii) Toluene-4-sulfonic acid 2-(1-benzyl-3-methyl-ureido)-ethyl ester

nBuLi (2.8 N, 1.01 g, 0.0157 mol) was added at −78° C. to a solution of1-benzyl-1-(2-hydroxy-ethyl)-3-methyl-urea (3 g, 0.0143 mol, from (i)above) in 30 ml of dry THF and stirred at same temperature for 30 minunder nitrogen atmosphere. P-Toluenesulfonyl chloride (3 g, 0.0157 mol)in 20 ml of dry THF was added dropwise at −78° C. and stirred for 3 hunder nitrogen atmosphere. The reaction was quenched with methanol andsolvent evaporated under reduced pressure. The crude was purified bycolumn chromatography over silica gel using 12% methanol indichloromethane as eluent to yield 2.5 g of the title compound as asolid.

Preparation S Ethanesulfonic acid 2-(benzyl-ethanesulfonyl-amino)-ethylester

Ethanesulfonyl chloride (2.1 g, 16.6 mmol) was added dropwise at 0° C.to a well-stirred solution of N-benzyl ethanolamine (1 g, 6.6 mmol) andtriethylamine (2.8 ml. 19 mmol) in dry dichloromethane (10 ml). Thereaction mixture was stirred at room temperature for 1 h and quenchedwith water. The compound was extracted with dichloromethane, the organiclayer was washed with water, brine and dried over sodium sulfate.Solvent evaporation under reduced pressure, followed by columnchromatography over silica gel using 2% methanol in chloroform as eluentafforded (0.8 g) of the title compound as a liquid.

EXAMPLES Example 1N-[2-(7-Benzyl-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl)ethyl]-N-[2-(4-cyanophenoxy)ethyl]urea

3-Benzyl-9-oxa-3,7-diaza-bicyclo[3.3.1]nonane (0.18 g, 0.82 mmol; see WO01/28992) and toluene-4-sulfonic acid2-{1-[2-(4-cyanophenoxy)ethyl]-ureido}ethyl ester (0.50 g, 1.24 mmol;see Preparation D above) were mixed in dry acetonitrile (15 mL) andstirred at 60° C. overnight. DCM (10 mL) was added, together with 0.5 gof PS—NCO (polymer-supported isocyanate). The mixture was stirred for 2h, then filtered and evaporated. The crude product was put on a SCX-II(cat ion exchanger)-plug, which plug was then eluted withDCM:MeOH(NH₃-saturated), 80:20. The product was further purified on aHorizon prep. column (40 g, A: DCM (1% MeOH), B: DCM/MeOH(NH₃-sat.),80:20. Gradient 0-30% B over 1080 mL). The product was then furtherpurified by prep. HPLC and finally extracted with DCM/Na₂CO₃ (aq.) togive 193 mg (51.9%) of the title compound.

¹³C NMR (100.6 MHz, CDCl₃) δ 162.2, 161.5, 136.2, 134.3, 129.9, 128.6,127.7, 119.3, 115.3, 104.4, 68.6, 67.9, 64.2, 61.4, 57.3, 56.1, 49.2,48.7

Example 2N-[2-(7-Benzyl-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl)ethyl]-N-[2-(4-cyanophenoxy)ethyl]methanesulfonamide,tartaric acid salt

Methanesulfonic acid2-{[2-(4-cyanophenoxy)ethyl]methanesulfonylamino}ethyl ester (0.60 g,1.65 mmol; see Preparation C(iii) above) and3-benzyl-9-oxa-3,7-diaza-bicyclo[3.3.1]nonane (0.36 g, 1.65 mmol; see WO01/28992) were mixed in acetonitrile (12 mL). The resulting solution wasdivided into 3 equal parts, which were put in microwave vessels. K₂CO₃(0.11 g, 0.46 mmol) was added to each vessel and the reaction was run inthe microwave reactor for 10 minutes at 160° C. The reaction mixtureswere filtered, combined and then put on a 5 g SCX-plug. The plug waswashed with DCM, acetonitrile and DCM:MeOH (80:20) until all(relatively) apolar material had been eluted. The product was theneluted with DCM:MeOH(NH₃-satd.) 80:20. Analysis by ¹H NMR showedresidual oxabispidine starting material, and so the product wasdissolved in DCM (30 mL) and 300 mg of polymer-supported isocyanate wasadded. The resulting mixture was then stirred overnight. Filtration andevaporation gave 450 mg of the pure, free base product. This product wasthen dissolved in ethanol, to which was added 1 equivalent (148.6 mg) oftartaric acid. The resulting mixture was evaporated and dissolved inwater. Freeze-drying overnight then gave 623 mg (59%) of the titlecompound as a colourless powder.

¹³C NMR (free base, 100.6 MHz, CDCl₃) δ 161.7, 137.7, 134.3, 129.3,128.5, 127.3, 119.2, 115.3, 104.8, 68.6, 67.6, 63.8, 59.0, 56.6, 56.4,47.0, 44.9, 39.3

Example 3N-[2-(4-Cyanophenoxy)ethyl]-N-{2-[7-(4-fluorobenzyl)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl]ethyl}methanesulfonamide(i)7-(2-{[2-(4-Cyanophenoxy)ethyl]methanesulfonylamino}ethyl)-9-oxa-3,7-diazabicyclo[3.3.1]nonane-3-carboxylicacid tert-butyl ester

To a suspension ofN-(2-bromoethyl)-N-[2-(4-cyanophenoxy)ethyl]methane-sulfonamide (6 g,0.019 mol; see Preparation C above) and anhydrous potassium carbonate(3.6 g, 0.026 mol) in dry acetonitrile (100 mL) was added9-oxa-3,7-diaza-bicyclo[3.3.1]nonane-3-carboxylic acid tert-butyl ester(4.35 g, 0.019 mol; see WO 01/28992), and the resultant mixture was thenstirred at 50-55° C. overnight. After completion of the reaction (asdetermined by TLC), the mixture was filtered and concentrated. The crudeproduct was further purified by column chromatography (silica gel:60-120 mesh, eluent: chloroform-methanol, 99:1). Yield: 4.2 g (46%).

(ii) N-[2-(4-Cyanophenoxy)ethyl]-N-[2-(9-oxa-3,7-diazabicyclo F3.3.1non-3-yl)ethyl]methanesulfonamide

To a saturated solution of HCl_((g)) in dioxane (100 mL) was added7-(2-{[2-(4-cyanophenoxy)ethyl]methanesulfonylamino}ethyl)-9-oxa-3,7-diazabicyclo[3.3.1]nonane-3-carboxylicacid tert-butyl ester (3.5 g, 0.0070 mol; see step (i) above), afterwhich the reaction was stirred for 1 h. On completion of the reaction(as determined by TLC), dioxane was decanted and product (semi-solid)dissolved in methanol (25 mL). After concentrating the methanol, dryether (50 mL) was added and the solvent was again concentrated. This wasrepeated twice and finally the product was dried under high vacuum.Yield: 3.0 g (99%).

(iii)N-[2-(4-Cyanophenoxy)ethyl]-N-{2-[7-(4-fluorobenzyl)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl]ethyl}methanesulfonamide

N-[2-(4-Cyanophenoxy)ethyl]-N-[2-(9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl)ethyl]methanesulfonamide(0.079 g, 0.2 mmol; see step (ii) above) and1-bromomethyl-4-fluorobenzene (0.040 g, 0.21 mmol) and K₂CO₃ (0.041 g,0.3 mmol) were was mixed in a microwave vessel and then heated in themicrowave reactor for 15 min at 160° C. The mixture was filtered and puton a SCX-II plug. The plug was washed with DCM, acetonitrile, DCM/MeOH(80:20), after which the product was eluted with DCM:MeOH(NH₃-satd.),80:20. The product was purified on a 9 g Horizon prep. chromatographycolumn (A:DCM(1% MeOH), B:DCM/MeOH(NH₃-satd.), 80:20. Gradient 0-25% B,270 mL (9 mL fractions)), which gave 63 mg (62.7%) of the titlecompound.

¹³C NMR (125.7 MHz, CDCl₃) δ 160.5, 159.1, 158.6, 131.8, 130.9, 128.1,128.0, 116.6, 112.8, 112.7, 112.6, 102.3, 65.9, 65.0, 60.3, 56.3, 54.0,53.7, 44.4, 42.6, 36.6

Example 4N-[2-(4-Cyanophenoxy)ethyl]-N-{2-[7-(pyridin-3-ylmethyl)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl]ethyl}methanesulfonamide

N-[2-(4-Cyanophenoxy)ethyl]-N-[2-(9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl)ethyl]methanesulfonamide(79 mg, 0.2 mmol; see Example 3(ii) above) and pyridine-3-carbaldehyde(36 mg, 0.34 mmol) were dissolved in DCM (4 mL) and shaken for 1.5 h.Sodium triacetoxyborohydride (144 mg, 0.68 mmol) was added and themixture was shaken overnight. The reaction was quenched with 1 M K₂CO₃(2 mL) and was then phase-separated. The aqueous layer was washed withDCM (3×3 mL) and the organic layers were combined and evaporated. Theresidue was purified by chromatography on silica, which gave 66 mg (68%)of the title compound.

¹³C NMR (125.7 MHz, CDCl₃) δ 161.7, 150.6, 148.7, 136.7, 134.4, 133.4,123.5, 119.2, 115.35, 104.8, 68.5, 67.6, 60.9, 58.8, 58.5, 56.9, 56.6,56.3, 47.1, 45.4, 39.1

Example 57-(2-{1-[2-(4-Cyanophenoxy)ethyl]-3,3-dimethylureido}ethyl)-9-oxa-3,7-diazabicyclo[3.3.1]nonane-3-carboxylicacid tert-butyl ester

1-[2-(4-Cyanophenoxy)ethyl]-3,3-dimethyl-1-(2-oxoethyl)urea (4.5 g; seePreparation G above) was taken in dichloromethane (100 mL).9-Oxa-3,7-diazabicyclo[3.3.1]nonane-3-carboxylic acid tert-butyl ester(2.9 g, 0.013 mol; see WO 01/28992), followed by glacial acetic acid(1.47 g, 0.0245 mol), was added, and reaction mixture was stirred for 1h. NaBH₃CN (1.54 g, 0.024 mol) was added at 0° C., and stirring wascontinued overnight at room temperature. The reaction mixture wasdiluted with water and extracted with dichloromethane. The organic layerwas washed with water and brine and then dried over sodium sulfate.Solvent evaporation, followed by purification by column chromatography,yielded the title compound (6.5 g).

¹H NMR (CDCl₃, 300 MHz), δ 7.59 (d, 2H), 6.95 (d, 2H), 4.14-4.08 (m,4H), 3.82-3.77 (m, 2H), 3.58-3.49 (3H, m), 3.30-3.27 (m, 4H), 2.92-2.80(m, 7H), 2.6-2.3 (m, 4H), 1.45 (s, 9H)

Example 67-(2-{1-[2-(4-Cyanophenoxy)ethyl]-3-methylureido}ethyl)-9-oxa-3,7-diazabicyclo[3.3.1]nonane-3-carboxylicacid tert-butyl ester

A mixture of toluene-4-sulfonic acid2-{1-[2-(4-cyanophenoxy)ethyl]-3-methylureido}ethyl ester (1.35 g, 3.233mmol; see Preparation I above),9-oxa-3,7-diaza-bicyclo[3.3.1]nonane-3-carboxylic acid tert-butyl ester(1.48 g, 6.466 mmol; see WO 01/28992) and potassium carbonate (1.34 g,9.7 mmol) in dry acetonitrile (15 mL) was stirred at 45° C. for 24 h.The reaction mixture was diluted with 20 nm water and extracted withethyl acetate. The organic layer was washed with water, brine and driedover sodium sulfate. Solvent evaporation under reduced pressure followedby column chromatography over silica gel (using 2-2.5% methanol indichloromethane) and further purification by preparative HPLC yielded920 mg of the title compound as a white solid.

MS: 474 (M⁺+H): calculated for C₂₄H₃₅N₅O₅ (M⁺+H) 474.

Example 77-(2-{1-[3-(4-Cyanophenyl)propyl]-3,3-dimethylureido}ethyl)-9-oxa-3,7-diazabicyclo[3.3.1]nonane-3-carboxylicacid tert-butyl ester

1-[3-(4-Cyanophenyl)propyl]-3,3-dimethyl-1-(2-oxoethyl)urea (6.5 g; seePreparation K above) was taken in dichloromethane (100 mL), to which wasadded 9-oxa-3,7-diaza-bicyclo[3.3.1]nonane-3-carboxylic acid tert-butylester (4.36 g, 0.019 mol; see WO 01/28992), followed by glacial aceticacid (2.14 g, 0.0357 mol). The reaction mixture was stirred for 1 hbefore NaBH₃CN (2.24 g, 0.0357 mol) was added at 0° C. Stirring wascontinued overnight at room temperature. The reaction mixture wasquenched with water and extracted with dichloromethane. The organiclayer was washed with water and brine and dried over sodium sulfate.Solvent evaporation, followed by purification by column chromatographyover silica gel (using 2% methanol in dichloromethane) yielded 7.5 g ofthe title compound as a yellow, gummy liquid.

¹H NMR (CDCl₃, 300 MHz); δ 7.57 (d, 2H), 7.28 (d, 2H), 4.09-3.9 (m, 2H),3.80-3.74 (m, 2H), 3.23-3.1 (m, 6H), 2.88-2.78 (m, 4H), 2.75 (s, 6H),2.63 (t, 2H), 2.52 (t, 2H), 2.3-2.1 (m, 2H), 1.83 (t, 2H), 1.44 S, 9H)

Example 8N-Benzyl-N-{2-[7-(4-cyanobenzyl)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl]-ethyl}methanesulfonamide

To a suspension of NaH (60% in oil, 0.039 g, 1.64 mmol) in dry DMF (10mL) was addedN-{2-[7-(4-cyanobenzyl)-9-oxa-3,7-diazabicyclo[3.3.1]-non-3-yl]ethyl}methanesulfonamide(0.3 g, 0.82 mmol; see Preparation M above) at 0° C. The reactionmixture was stirred for 1 h at room temperature. Benzyl bromide (0.155g, 0.9 mmol) was added at 0° C. and the reaction mixture stirred at rtfor 2 h. The reaction quenched with water, extracted withdichloromethane, washed with water, brine and then dried over sodiumsulfate. Solvent evaporation under reduced pressure, followed by columnchromatography of the residue over silica gel (using 5% methanol inchloroform as eluent) gave 160 mg of the title compound as a pale yellowsolid.

¹³C NMR (75 MHz, CDCl₃): δ 143.76, 136.07, 132.059, 129.30, 128.74,128.14, 128.04, 118.83, 110.74, 68.17, 62.60, 57.70, 56.24, 55.94,53.32, 51.38, 43.89, 39.18.

Example 9N-(2-{7-[3-(4-Cyano-phenoxy)-propyl]-9-oxa-3,7-diaza-bicyclo[3.3.1]non-3-yl}-ethyl)-N-(2-phenoxy-ethyl)methanesulfonamide

(i) A suspension of4-[3-(9-oxa-3,7-diaza-bicyclo[3.3.1]non-3-yl)-propoxy]-benzonitrile (1.5g, 5.5 mmol, see WO 01/28992), methanesulfonic acid2-[methanesulfonyl-(2-phenoxy-ethyl)-amino]-ethyl ester (1.51 g, 4.5mmol, preparation P above) and dry K₂CO₃ (1.69 g, 12.3 mmol) in dryacetonitrile (100 ml) was stirred at 60° C. overnight under nitrogenatmosphere. The reaction mixture was filtered and solvent concentratedunder reduced pressure. The residue was purified by columnchromatography over silica gel using 3% methanol in dichloromethane aseluent to give the title compound (1.4 g) as a liquid.

¹H NMR (400 MHz, CD₃Cl₃) δ 7.57 (2H, d), 7.30 (2H, d), 7.03-6.89 (5H,m), 4.22-4.12 (8H, m), 4.03-4.00 (3H, bt), 3.79-3.71 (4H, m), 3.37 (2H,m), 3.12 (2H, m), 3.00 (3H, s) 2.85 (2H, m), 2.83-2.76 (2H, m), 2.50(2H, bs)

Example 10N-Benzyl-N-{2-[7-(4-cyano-benzyl)-9-oxa-3,7-diaza-bicyclo[3.3.1]non-3-yl]-ethyl}-benzenesulfonamide(i) Benzenesulfonic acid 2-(benzenesulfonyl-benzyl-amino)-ethyl ester

Benzenesulfonyl chloride (2.2 ml, 0.0175 mol) was added dropwise at 0°C. to a well-stirred solution of N-benzyl ethanolamine (1 g, 0.7 mmol)and triethylamine (2.4 ml. 0.0175 mol) in dry dichloromethane (10 ml).The reaction mixture was stirred at room temperature for 1 h andquenched with water. The compound was extracted with dichloromethane,organic layer was washed with water, brine and dried over sodiumsulfate. Solvent evaporation under reduced pressure afforded 0.6 g ofthe desired product as a solid. This was directly taken for next stepwithout further purification.

(ii)N-Benzyl-N-{2-[7-(4-cyano-benzyl)-9-oxa-3,7-diaza-bicyclo[3.3.1]non-3-yl]-ethyl}-benzenesulfonamide

A suspension of benzenesulfonic acid2-(benzenesulfonyl-benzyl-amino)-ethyl ester (0.33 g, 1.04 mmol, fromstep (i) above),4-(9-Oxa-3,7-diazabicyclo[3.3.1]non-3-ylmethyl)benzonitrile, hydrogenchloride salt (0.5 g, 1.16 mmol, from prep M (ii) above) and potassiumcarbonate (0.64 g, 4.64 mmol) in dry acetonitrile (10 ml) was stirred at60° C. overnight under nitrogen atmosphere. The reaction mixture wasfiltered and the filtrate was concentrated under reduced pressure. Theresidue was purified by column chromatography over silica gel using 10%methanol in dichloromethane as eluent to yield 80 mg of the titlecompound as a liquid.

¹H NMR (400 MHz, CDCl₃) δ 7.67-7.63 (1H, m), 7.58-7.50 (6H, m),7.30-7.27 (5H, m), 4.45 (2H, s), 3.85 (2H, bt), 3.72-3.64 (2H, bm), 3.37(2H, m), 3.0-2.89 (4H, bm), 2.75-2.16 (6H, bm)

Example 11N-{2-[7-(2-Cyano-benzyl)-9-oxa-3,7-diaza-bicyclo[3.3.1]non-3-yl]-ethyl}-N-[2-(4-cyano-phenoxy)-ethyl]-methanesulfonamide

ToN-[2-(4-cyano-phenoxy)-ethyl]-N-[2-(9-oxa-3,7-diaza-bicyclo[3.3.1]-non-3-yl)-ethyl]-methanesulfonamide(0.079 g, 0.20 mmol), 2-bromo-methyl-benzonitrile (0.041 g, 0.21 mmol)and anhydrous potassium carbonate (0.042 g, 0.30 mmol) was added dryacetonitrile (4 mL). The mixture was heated by microwave irradiation (15minutes, 160° C.) and was then filtered. The filtrate was loaded onto acation exchange column (SCX-2, Isolute™, 2 g). The column was washedwith dichloromethane, acetonitrile and dichloromethane/methanol 80:20before eluting the crude product with 20% methanol saturated withammonia in dichloromethane. The filtrate was concentrated in vacuo andthe crude product was purified by chromatography on silica gel usingmethanol saturated with ammonia in dichloromethane as eluent, whichafforded 57 mg (55.9%) of the title compound.

¹³C NMR (125.7 MHz, CDCl₃) δ 159.06, 139.57, 131.78, 130.64, 130.24,127.71, 125.27, 116.56, 115.58, 112.75, 110.56, 102.33, 65.84, 64.92,58.67, 55.85, 53.80, 53.58, 44.66, 43.17, 36.36

Example 12N-(4-Cyano-benzyl)-N-{2-[7-(4-cyano-benzyl)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl]-ethyl}-methanesulfonamide

To a suspension of sodium hydride (0.013 g of a 60% suspension inmineral oil, washed with pentane) in anhydrous N,N-dimethylformamide (4mL) was addedN-{2-[7-(4-Cyano-benzyl)-9-oxa-3,7-diaza-bicyclo[3.3.1]non-3-yl]-ethyl}-methanesulfonamide(0.109 g, 0.30 mmol) at 0° C. The mixture was stirred for 2 hours whilethe temperature was allowed to warm to room temperature. At 0° C.,4-bromomethyl-benzonitrile (0.065 g, 0.33 mmol) was added. The mixturewas stirred for 2 hours at room temperature, whereupon water (5 mL) wasadded. The aqueous layer was extracted with dichloromethane (3×5 mL) andthe combined organic layers were dried over Na₂SO₄ and concentrated invacuo. The crude product was purified by chromatography on silica gelusing methanol saturated with ammonia dichloromethane as eluent, whichafforded 79 mg (54.9%) of the title compound.

¹³C NMR (125.7 MHz, CDCl₃) δ 143.69, 142.72, 132.69, 132.46, 129.68,128.63, 119.13, 118.74, 112.01, 111.11, 68.40, 63.27, 57.99, 56.38,51.57, 44.95, 39.06

Example 13N-benzyl-N-{2-[7-(4-cyanobenzyl)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl]ethyl}-N′,N′-dimethylurea(i) 1-Benzyl-1-(2-hydroxy-ethyl)-3,3-dimethyl-urea

N,N-dimethyl carbamoyl chloride (2.55 g, 0.0238 mol) was added drop bydrop at 0° C. to a solution of N-benzyl ethanol amine (3 g, 0.0198 mol)and triethylamine (3 g, 0.0298 mol) in 25 ml of DCM (dry) and stirred atRT for 3 h under nitrogen atmosphere. The reaction was quenched withwater, extracted with dichloromethane, washed with water, brine anddried over sodium sulfate. Solvent evaporation under reduced pressurefollowed by column chromatography over silica gel using 3.5% methanol indichloromethane as eluent afforded 4 g of the sub-title compound as aliquid.

(ii)N-benzyl-N-{2-[7-(4-cyanobenzyl)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl]ethyl}-N′,N′-dimethylurea

Oxalyl chloride (1.14 g, 9 mmol) was added at −78° C. to a solution ofDMSO (1.05 g, 13.5 mmol) in dry dichloromethane (10 ml) and stirred for30 min. 1-Benzyl-1-(2-hydroxy-ethyl)-3,3-dimethyl-urea (1.05 g, 13.5mmol; from step (i) above) in dry dichloromethane (10 ml). (1 g, 4.5mmol) was added dropwise at same temperature and stirring continued for3 h at the same temperature. Triethylamine (1.8 ml, 12.9 mmol) was addedat −78° C. and the reaction mixture was warmed to −30° C. Reactionmixture was quenched with 10% aq. citric acid (10 ml) and extracted withdichloromethane. The organic layer was washed with brine and dried oversodium sulfate. Solvent evaporation under reduced pressure yielded 0.79g of crude aldehyde as a liquid.

This (0.75 g, 3.4 mmol) was then taken in DCM (25 ml),4-(9-Oxa-3,7-diazabicyclo[3.3.1]non-3-ylmethyl)benzonitrile (960 mg, 3.4mmol) was added at 0° C. The reaction mixture was stirred at RTovernight, quenched with water and extracted with dichloromethane.Organic layer was washed with water and brine and dried over sodiumsulfate. Solvent evaporation under reduced pressure followed bypurification by column chromatography over silica gel using 6.5%methanol in dichloromethane as eluent yielded 0.5 g of the desiredproduct. This was further purified by prep HPLC to give 0.3 g of thetitle compound as off white solid.

API-MS: (M+1)=448

Example 14N-benzyl-N-{2-[7-(4-cyanobenzyl)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl]ethyl}acetamide(i) N-Benzyl-N-(2-hydroxy-ethyl)-acetamide

Acetyl chloride (0.858 g, 10.8 mmol) was added drop by drop to asolution of N-benzyl ethanol amine (1.5 g, 9.9 mmol) and triethylamine(1.5 g, 14.9 mmol) in dry dichloromethane (20 ml) at 0° C. undernitrogen atmosphere and stirred at room temperature overnight. Thereaction was quenched with water and extracted with dichloromethane. Theorganic layer was washed with water, 10% aq. NaHCO₃, brine and driedover sodium sulfate. Solvent evaporation under reduced pressure,followed by column chromatography over silica gel using 5% methanol indichloromethane as eluent afforded 0.68 g of the desired product as anoil.

(ii)N-benzyl-N-{2-[7-(4-cyanobenzyl)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl]ethyl}acetamide

Oxalyl chloride (0.57 g, 4.5 mmol) was added at −78° C. to a solution ofDMSO (0.63 ml, 9 mmol) in dry dichloromethane (5 ml) and stirred for 15min. N-Benzyl-N-(2-hydroxy-ethyl)-acetamide (0.58 g, 3 mmol; from step(i) above) dissolved in dry dichloromethane (5 ml) was added dropwise atthe same temperature and stirring continued for 3 h at the sametemperature. Triethylamine (2.1 ml, 15 mmol) was added at −78° C. andthe reaction mixture was warmed to −30° C. Reaction mixture was quenchedwith 10% aq. citric acid (10 ml) and extracted with dichloromethane. Theorganic layer was washed with brine and dried over sodium sulfate.Solvent evaporation under reduced pressure yielded 0.51 g of crudealdehyde. This (0.51 g, 2.6 mmol) was then taken in DCM (10 ml),4-(9-Oxa-3,7-diazabicyclo[3.3.1]non-3-ylmethyl)benzonitrile, hydrogenchloride salt (0.57 g, 2.6 mmol; from step M (ii) above) and molecularsieves (500 mg) and stirred for 1 h at room temperature. NaBH₃CN (0.24g, 3.9 mmol) was added at 0° C. and stirring continued overnight undernitrogen atmosphere. The reaction was quenched with water and extractedwith dichloromethane. The organic layer was washed with water and brineand dried over sodium sulfate. Solvent evaporation under reducedpressure followed by purification by column chromatography (two times)over silica gel using 3% methanol in dichloromethane as eluent yielded430 mg desired product. This (430 mg) was again purified by prep HPLCusing 1% acetic acid in acetonitrile as eluent. Acetonitrile was thenevaporated under reduced pressure and the residue was partitionedbetween 10% NaHCO₃ and DCM. Organic layer was then washed with water andbrine and dried over sodium sulfate. Solvent evaporation under reducedpressure afforded (150 mg) of the title compound as a liquid.

API-MS: (M+1)=419

Example 15N-benzyl-N-{2-[7-(4-cyanobenzyl)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl]ethyl}propane-2-sulfonamide(i) Benzyl-(2-hydroxy-ethyl)-carbamic acid tert-butyl ester

(Boc)₂O (7.9 g, 0.036 mol) was added drop by drop at 0° C. to a solutionof N-benzyl ethanol amine (5 g, 0.033 mol) in dry dichloro methane (50ml) and stirred at room temperature overnight under nitrogen atmosphere.The reaction was quenched with water, extracted with dichloromethane,washed with brine and dried over sodium sulfate. Solvent evaporationunder reduced pressure followed by purification over silica gel using10% ethyl acetate in petroleum ether as eluent afforded the sub-titlecompound (3.2 g) as an oil.

(ii)Benzyl-{2-[7-(4-cyano-benzyl)-9-oxa-3,7-diaza-bicyclo[3.3.1]non-3-yl]-ethyl}-carbamicacid tert-butyl ester

Dry DMSO (1.8 g, 0.0237 mol) was added to a solution of oxalyl chloride(1.5 g, 0.01185 mol) in dry dichloro methane (25 ml) at −78° C. andstirred for 10 min. Benzyl-(2-hydroxy-ethyl)-carbamic acid tert-butylester (2 g, 0.0079 mol; from (i) above) in 15 ml of DCM was addeddropwise at the same temperature and stirring continued at sametemperature for 3 h. Triethylamine (5.5 ml) was added, the reactionmixture was warmed to −30° C. and quenched with 10% aq. citric acid. Thecompound was extracted with dichloromethane, washed with water and brineand dried over sodium sulfate. Solvent evaporation under reducedpressure afforded the desired aldehyde (2.5 g) as an liquid. This (2.5g, 10 mmol) was then added to a mixture of4-(9-oxa-3,7-diazabicyclo[3.3.1]non-3-ylmethyl)benzonitrile, hydrogenchloride salt (1.98 g, 8 mmol, from. M(i) above) and MgSO₄ (2 g) in drydichloromethane (10 ml) and stirred for 4 h under nitrogen atmosphere.Methanol (10 ml), followed by NaBH₃CN (0.76 g, 12 mmol) was added andthe reaction mixture was stirred overnight. The reaction was quenchedwith water, extracted with dichloromethane, washed with brine and driedover sodium sulfate. Solvent evaporation under reduced pressure followedby purification over silica gel using 3% methanol in chloroform aseluent afforded the desired product (1.1 g) as an off white solid.

(iii)4-[7-(2-Benzylamino-ethyl)-9-oxa-3,7-diaza-bicyclo[3.3.1]non-3-ylmethyl]-benzonitrile

Dioxane saturated with HCl gas (10 ml) was added to a solution ofbenzyl-{2-[7-(4-cyano-benzyl)-9-oxa-3,7-diaza-bicyclo[3.3.1]non-3-yl]-ethyl}-carbamicacid tert-butyl ester (0.65 g, from step (ii) above in 5 ml of dioxaneand stirred for 1 h at RT under nitrogen atmosphere. The reactionmixture was diluted with dry diethylether, and the solvent was decanted.Precipitated solid was washed with dry diethylether (4 times) and driedunder vacuum to give HCl salt of the sub-title compound (0.5 g) as apowder.

(iv)N-benzyl-N-{2-[7-(4-cyanobenzyl)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl]ethyl}propane-2-sulfonamide

4-[7-(2-Benzylamino-ethyl)-9-oxa-3,7-diaza-bicyclo[3.3.1]non-3-ylmethyl]-benzonitrile(0.5 g, 1.33 mmol, from step (iii) above) was taken in 30 ml of DCM/10%aq. NaHCO₃ (1:1) and stirred for 15 min. Isopropane sulfonyl chloride(0.28 g, 1.99 mmol) was added and stirring continued at RT for 1.5 h.The organic layer was separated, washed with brine and dried over sodiumsulfate. Solvent evaporation under reduced pressure followed bypurification over silica gel using 10% ethyl acetate in petroleum etheras eluent afforded the desired product (280 mg) as white solid. This wasfurther purified by prep HPLC (0.1% TFA in acetonitrile), evaporatedunder reduced pressure, and the residue was partitioned between satNaHCO₃ and DCM. The organic layer was washed with brine and dried oversodium sulfate. Solvent evaporation under reduced pressure afforded thetitle compound (140 mg) as an off-white solid.

API-MS: (M+1)=483

Example 16

The following compounds were prepared, from appropriate intermediates(such as those described hereinbefore), according to or by analogy withmethods described herein:

-   (i) tert-butyl[2-(7-{2-[[2-(4-cyanophenoxy)ethyl]    (methylsulfonyl)-amino]ethyl}-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl)ethyl]-carbamate;-   (ii) tert-butyl {2-[7-(2-{(aminocarbonyl)    [2-(4-cyanophenoxy)ethyl]-amino}ethyl)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl]ethyl}-carbamate;-   (iii)    N-[2-(4-cyanophenoxy)ethyl]-N-(2-{7-[2-(4-methoxyphenyl)-2-oxoethyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}ethyl)methanesulfonamide;-   (iv)    N-[2-(4-cyanophenoxy)ethyl]-N-(2-{7-[2-(4-methoxyphenyl)-2-oxoethyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}ethyl)urea;-   (v) 2-[7-(2-{(aminocarbonyl)    [2-(4-cyanophenoxy)ethyl]amino}ethyl)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl]-N-(tert-butyl)acetamide;-   (vi)    2-[7-(2-{(aminocarbonyl)[2-(4-cyanophenoxy)ethyl]amino}ethyl)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl]-N-benzylacetamide;-   (vii) 2-[7-(2-{(aminocarbonyl)    [2-(4-cyanophenoxy)ethyl]amino}ethyl)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl]-N-(1-methyl-1-phenylethyl)acetamide;-   (viii) N-(tert-butyl)-2-(7-{2-[[2-(4-cyanophenoxy)ethyl]    (methylsulfonyl)amino]ethyl}-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl)acetamide;-   (ix)    N-benzyl-2-(7-{2-[[2-(4-cyanophenoxy)ethyl](methylsulfonyl)-amino]ethyl}-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl)acetamide;-   (x)    2-(7-{2-[[2-(4-cyanophenoxy)ethyl](methylsulfonyl)amino]ethyl}-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl)-N-(1-methyl-1-phenylethyl)acetamide;-   (xi)    tert-butyl[2-(7-{2-[[3-(4-cyanophenyl)propyl](methylsulfonyl)-amino]ethyl}-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl)ethyl]-carbamate;-   (xii)    N-(tert-butyl)-2-(7-{2-[[3-(4-cyanophenyl)propyl](methylsulfonyl)-amino]ethyl}-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl)acetamide;-   (xiii)    N-[2-(7-benzyl-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl)ethyl]-N-[3-(4-cyanophenyl)propyl]methanesulfonamide;-   (xiv)    N-[2-(4-cyanophenoxy)ethyl]-N-(2-{7-[2-(2,6-dimethylphenoxy)ethyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}ethyl)urea;-   (xv)    N-[2-(4-cyanophenoxy)ethyl]-N-(2-{7-[2-(4-cyanophenyl)ethyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}ethyl)urea;-   (xvi)    N-[2-(4-cyanophenoxy)ethyl]-N-(2-{7-[2-(4-methoxyphenyl)ethyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}ethyl)urea;-   (xvii)    N-(2-{7-[2-(4-acetylphenyl)ethyl]-9-oxa-3,7-diazabicyclo-[3.3.1]non-3-yl}ethyl)-N-[2-(4-cyanophenoxy)ethyl]urea;-   (xviii)    N-[2-(4-cyanophenoxy)ethyl]-N-{2-[7-(2-phenylethyl)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl]ethyl}urea;-   (xix)    N-[2-(4-cyanophenoxy)ethyl]-N-(2-{7-[2-(3-fluorophenyl)ethyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}ethyl)urea;-   (xx)    N-(2-{7-[(2-chloropyridin-3-yl)methyl]-9-oxa-3,7-diazabicyclo-[3.3.1]non-3-yl}ethyl)-N-[2-(4-cyanophenoxy)ethyl]methanesulfonamide;-   (xxi)    N-[2-(4-cyanophenoxy)ethyl]-N-(2-{7-[(6-methoxypyridin-3-yl)methyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}ethyl)methanesulfonamide;-   (xxii)    N-[2-(4-cyanophenoxy)ethyl]-N-(2-{7-[(4,5-dimethyl-2-furyl)methyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}ethyl)methanesulfonamide;-   (xxiii)    N-[2-(4-cyanophenoxy)ethyl]-N-(2-{7-[4-(trifluoromethyl)benzyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}ethyl)methanesulfonamide;-   (xxiv)    N-{2-[7-(4-chlorobenzyl)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl]ethyl}-N-[2-(4-cyanophenoxy)ethyl]methanesulfonamide;-   (xxv)    N-[2-(4-cyanophenoxy)ethyl]-N-(2-{7-[4-(difluoromethoxy)benzyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}ethyl)methanesulfonamide;-   (xxvi)    N-[2-(4-cyanophenoxy)ethyl]-N-(2-{7-[4-(methylsulfonyl)benzyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}ethyl)methanesulfonamide;-   (xxvii)    N-[2-(4-cyanophenoxy)ethyl]-N-{2-[7-(2-fluorobenzyl)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl]ethyl}methanesulfonamide;-   (xxviii)    N-[2-(4-cyanophenoxy)ethyl]-N-{2-[7-(2,4-difluorobenzyl)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl]ethyl}methanesulfonamide;-   (xxix)    N-[2-(4-cyanophenoxy)ethyl]-N-{2-[7-(2,5-dichlorobenzyl)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl]ethyl}methanesulfonamide;-   (xxx)    N-[2-(4-cyanophenoxy)ethyl]-N-(2-{7-[3-(trifluoromethyl)benzyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}ethyl)methanesulfonamide;-   (xxxi)    N-{2-[7-(4-cyanobenzyl)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl]ethyl}-N-[2-(4-cyanophenoxy)ethyl]methanesulfonamide;-   (xxxii)    N-[2-(4-cyanophenoxy)ethyl]-N-(2-{7-[(2,6-dichloropyridin-4-yl)methyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}ethyl)methanesulfonamide;-   (xxxiii)    N-[2-(4-cyanophenoxy)ethyl]-N-{2-[7-(pyridin-4-ylmethyl)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl]ethyl}methanesulfonamide;-   (xxxiv)    N-[2-(4-cyanophenoxy)ethyl]-N-(2-{7-[(3,5-dimethylisoxazol-4-yl)methyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}ethyl)methanesulfonamide;-   (xxxv)    N-[2-(4-cyanophenoxy)ethyl]-N-(2-{7-[(2,4-dimethyl-1,3-thiazol-5-yl)methyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}ethyl)methanesulfonamide;-   (xxxvi)    N-[2-(4-cyanophenoxy)ethyl]-N-(2-{7-[(1-methyl-1H-imidazol-2-yl)methyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}ethyl)methanesulfonamide;-   (xxxvii)    N-[2-(4-cyanophenoxy)ethyl]-N-{2-[7-(3-phenylpropyl)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl]ethyl}methanesulfonamide;-   (xxxviii)    N-[2-(4-cyanophenoxy)ethyl]-N-(2-{7-[3-(4-cyanophenyl)propyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}ethyl)methanesulfonamide;-   (xxxix)    N-[2-(4-cyanophenoxy)ethyl]-N-(2-{7-[3-(3-methoxyphenyl)propyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}ethyl)methanesulfonamide;-   (xl)    N-[2-(4-cyanophenoxy)ethyl]-N-{2-[7-(2,6-dimethylbenzyl)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl]ethyl}methanesulfonamide;-   (xli)    N-{2-[7-(4-tert-butylbenzyl)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl]ethyl}-N-[2-(4-cyanophenoxy)ethyl]methanesulfonamide;-   (xlii)    N-[2-(7-benzyl-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl)ethyl]-N-[2-(4-cyanophenoxy)ethyl]-N′,N′-dimethylurea;-   (xliii)    N-{2-[7-(4-cyanobenzyl)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl]ethyl}-N-[2-(4-cyanophenoxy)ethyl]-N′,N′-dimethylurea;-   (xliv)    N-[2-(4-cyanophenoxy)ethyl]-N-(2-{7-[2-fluoro-4-(trifluoromethyl)benzyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}ethyl)-N′,N′-dimethylurea;-   (xlv)    N-[2-(4-cyanophenoxy)ethyl]-N-{2-[7-(4-fluorobenzyl)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl]ethyl}-N′,N′-dimethylurea;-   (xlvi)    N-[2-(4-cyanophenoxy)ethyl]-N-(2-{7-[4-(difluoromethoxy)benzyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}ethyl)-N′,N′-dimethylurea;-   (xlvii)    N-[2-(4-cyanophenoxy)ethyl]-N′,N′-dimethyl-N-{2-[7-(2-phenylethyl)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl]ethyl}urea;-   (xlviii)    N-[2-(4-cyanophenoxy)ethyl]-N-(2-{7-[2-(4-cyanophenyl)ethyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}ethyl)-N′,N′-dimethylurea;-   (xlix)    N-[2-(4-cyanophenoxy)ethyl]-N-(2-{7-[2-(3-fluorophenyl)ethyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}ethyl)-N′,N′-dimethylurea;-   (l)    N-[2-(4-cyanophenoxy)ethyl]-N′,N′-dimethyl-N-{2-[7-(3-phenylpropyl)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl]ethyl}urea;-   (li)    N-[2-(4-cyanophenoxy)ethyl]-N-{2-[7-(2-phenylethyl)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl]ethyl}methanesulfonamide;-   (lii)    N-[2-(4-cyanophenoxy)ethyl]-N-(2-{7-[2-(4-cyanophenyl)ethyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}ethyl)methanesulfonamide;-   (liii)    N-[2-(4-cyanophenoxy)ethyl]-N-(2-{7-[2-(4-fluorophenyl)ethyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}ethyl)methanesulfonamide;-   (liv)    N-benzyl-N-(2-{7-[2-(4-cyanophenoxy)ethyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}ethyl)methanesulfonamide;-   (lv)    N-(2-{7-[2-(4-cyanophenoxy)ethyl]-9-oxa-3,7-diazabicyclo-[3.3.1]non-3-yl}ethyl)-N-(2-phenylethyl)methanesulfonamide;-   (lvi)    N-(2-{7-[3-(4-cyanophenoxy)propyl]-9-oxa-3,7-diazabicyclo-[3.3.1]non-3-yl}ethyl)-N-(2-phenylethyl)methanesulfonamide;-   (lvii)    N-(2-{7-[2-(4-cyanophenoxy)ethyl]-9-oxa-3,7-diazabicyclo-[3.3.1]non-3-yl}ethyl)-N-(2-phenoxyethyl)methanesulfonamide;-   (lviii)    N-{2-[7-(4-cyanobenzyl)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl]ethyl}-N-(2-phenoxyethyl)methanesulfonamide;-   (lix)    N-{2-[7-(4-cyanobenzyl)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl]ethyl}-N-(2-phenylethyl)methanesulfonamide;-   (lx)    N-(2-{7-[3-(4-cyanophenoxy)propyl]-9-oxa-3,7-diazabicyclo-[3.3.1]non-3-yl}ethyl)-N-(2-phenoxyethyl)methanesulfonamide;-   (lxi)    N-benzyl-N-{2-[7-(4-fluorobenzyl)-9-oxa-3,7-diazabicyclo-[3.3.1]non-3-yl]ethyl}methanesulfonamide;-   (lxii)    N-benzyl-N-{2-[7-(4-chlorobenzyl)-9-oxa-3,7-diazabicyclo-[3.3.1]non-3-yl]ethyl}methanesulfonamide;-   (lxiii)    N-(2-cyanobenzyl)-N-{2-[7-(4-cyanobenzyl)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl]ethyl}methanesulfonamide;-   (lxiv)    N-{2-[7-(4-cyanobenzyl)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl]ethyl}-N-(4-fluorobenzyl)methanesulfonamide;-   (lxv)    N-{2-[7-(4-cyanobenzyl)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl]ethyl}-N-(3-fluorobenzyl)methanesulfonamide;-   (lxvi)    N-{2-[7-(4-cyanobenzyl)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl]ethyl}-N-[4-(difluoromethoxy)benzyl]methanesulfonamide;-   (lxvii)    N-(4-chlorobenzyl)-N-{2-[7-(4-cyanobenzyl)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl]ethyl}methanesulfonamide;-   (lxviii)    N-benzyl-N-{2-[7-(4-cyanobenzyl)-9-oxa-3,7-diazabicyclo-[3.3.1]non-3-yl]ethyl}ethanesulfonamide;-   (lxix)    N-benzyl-N-{2-[7-(4-cyanobenzyl)-9-oxa-3,7-diazabicyclo-[3.3.1]non-3-yl]ethyl}-N′-methylurea;-   (lxx)    N-benzyl-N-(2-{7-[2-(4-cyanophenyl)ethyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}ethyl)methanesulfonamide;-   (lxxi)    N-benzyl-N-(2-{7-[2-(2,4-dicyanophenoxy)ethyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}ethyl)methanesulfonamide;-   (lxxii)    N-benzyl-N-(2-{7-[3-(4-cyanophenoxy)propyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}ethyl)methanesulfonamide;-   (lxxiii)    N-benzyl-N-{2-[7-(4-cyanobenzyl)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl]ethyl}-1,1,1-trifluoromethanesulfonamide;-   (lxxiv)    N-benzyl-N-{2-[7-(4-cyanobenzyl)-9-oxa-3,7-diazabicyclo-[3.3.1]non-3-yl]ethyl}urea;    and-   (lxxv)    N-{2-[7-(4-cyanobenzyl)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl]ethyl}-N-(4-fluorobenzyl)urea;

or a pharmaceutically acceptable derivative thereof.

Example 17

Title compounds of the above Examples were tested in Test A above andwere found to exhibit D₁₀ values of more than 5.5.

Example 18

Title compounds of the above Examples were tested in Test B above andwere found to exhibit pIC₅₀ values of greater than 4.5. Indeed thecompounds of Examples 2, 3 and 9(xlvi) were found to have pIC₅₀ valuesof 5.55, 5.8 and 5.38, respectively.

Abbreviations

-   Ac=acetyl-   API=atmospheric pressure ionisation (in relation to MS)-   aq.=aqueous-   br=broad (in relation to NMR)-   Bt=benzotriazole-   t-BuOH=tert-butanol-   CI=chemical ionisation (in relation to MS)-   MCPBA=meta-chloroperoxybenzoic acid-   d=doublet (in relation to NMR)-   DBU=diazabicyclo[5.4.0]undec-7-ene-   DCM=dichloromethane-   dd=doublet of doublets (in relation to NMR)-   DMAP=4-dimethylaminopyridine-   DMF=N,N-dimethylformamide-   DMSO=dimethylsulfoxide-   EDC=1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide-   Et=ethyl-   EtOAc=ethyl acetate-   eq. equivalents-   ES=electrospray (in relation to MS)-   FAB=fast atom bombardment (in relation to MS)-   FBS=foetal bovine serum-   h=hour(s)-   HCl=hydrochloric acid-   HEPES=4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid-   HPLC=high performance liquid chromatography-   IMS=industrial methylated spirits-   IPA=iso-propyl alcohol (propan-2-ol)-   m=multiplet (in relation to NMR)-   Me=methyl-   MeCN=acetonitrile-   MeOH=methanol-   min.=minute(s)-   m.p.=melting point-   MS=mass spectroscopy-   NADPH=nicotinamide adenine dinucleotide phosphate, reduced form-   OAc=acetate-   Pd/C=palladium on carbon-   q=quartet (in relation to NMR)-   rt=room temperature-   S=singlet (in relation to NMR)-   t=triplet (in relation to NMR)-   TEA=triethylamine-   TIPE=tetrahydrofuran-   tlc=thin layer chromatography    Prefixes n-, s-, i-, t- and tert- have their usual meanings: normal,    secondary, iso, and tertiary.

1-38. (canceled)
 39. A compound of formula I

wherein: G represents CH or N; R⁴¹ to R⁴⁶, independently, represent H orC₁₋₃ alkyl; A represents C₂₋₆ alkylene optionally interrupted by—S(O)₂N(R^(18a))— or —N(R)SO₂— and/or optionally substituted by one ormore substituents selected from —OH, halo, and amino; R^(18a) representsH or C₁₋₆ alkyl; R² represents —S(O)₂R^(3a), —C(O)OR^(3b), —C(O)R^(3c),—C(O)N(R^(3d))(R^(3e)) or —S(O)₂N(R^(3f))(R^(3g)); R^(3a) to R^(3g),independently, represent C₁₋₆ alkyl (optionally substituted by one ormore substituents selected from halo, -E-aryl, -E-Het⁸, —C(O)R^(16a),—C(O)OR^(16b) and —C(O)N(R^(16c))R^(16d)), aryl or Het⁹, or R^(3c) andR^(3d) to R^(3g) independently represent H; E represents, at eachoccurrence when used herein, a direct bond or C₁₋₄ alkylene; Het¹ toHet¹¹, independently, represent five- to twelve-membered heterocyclicgroups containing one or more heteroatoms selected from oxygen nitrogenand/or sulfur, which groups are optionally substituted by one or moresubstituents selected from —OH, oxo, halo, cyano, nitro, C₁₋₆ alkyl,C₁₋₆ alkoxy, aryl, aryloxy, —N(R^(17a))R^(17b), —C(O)R^(17c),—C(O)OR^(17d), —C(O)N(R^(17e))R^(17f), —N(R^(17g))C(O)R^(17h),—S(O)N(R^(17i))R^(17j) and —N(R^(17k))S(O)₂R^(17l); R^(16a) to R^(16d),independently, represent at each occurrence when used herein, H, C₁₋₆alkyl (optionally substituted by one or more substituents selected fromhalo, aryl and Het¹⁰) aryl Het¹¹, or R^(16c) and R^(16d) togetherrepresent C₃₋₆ alkylene, optionally interrupted by an O atom; R^(17a) toR^(17l), independently, represent C₁₋₆ alkyl, aryl or R^(17a) to R^(17k)independently represent H; B represents-Z¹-{[C(O)]_(a)C(H)(R^(19a))}_(b)—, -Z²-[C(O)]_(c)N(R^(19b))—,-Z²-S(O)_(n)—, -Z²-N(R^(18c))S(O)₂—, -Z²-S(O)₂N(R^(18d))— or -Z²-O— (inwhich six groups Z¹ or Z² is attached to the nitrogen atom bearing R²);a, b, and c, independently, represent 0 or 1; n represents 0, 1 or 2; Z¹represents a direct bond or C₁₋₄ alkylene, optionally interrupted by—N(R^(18e))S(O)₂— or —S(O)₂N(R^(18f))—; Z² represents, at eachoccurrence when used herein, C₂₋₄ alkylene, optionally interrupted by—N(R^(18g))S(O)₂— or —S(O)N(R^(18h))—; R^(18c) to R^(18h),independently, represent H or C₁₋₆ alkyl; R^(19a) represents H or,together with a single R⁴ substituent at a position on the phenyl orpyridyl group that is ortho- to the position at which the group B isattached, R^(19a) represents C₂₋₄ alkylene optionally interrupted orterminated by O, S or N(R²⁰); R^(19b) represents H, C₁₋₆ alkyl or,together with a single R⁴ substituent at a position on the phenyl orpyridyl group that is ortho- to the position at which the group B isattached, R^(19b) represents C₂₋₄ alkylene; R²⁰ represents H or C₁₋₆alkyl R⁴ represents one or more optional substituents selected from —OH,cyano, halo, nitro, C₁₋₆ alkyl (optionally terminated by—N(H)C(O)OR^(21a)), C₁₋₆ alkoxy, —N(R^(22a))R^(22b), —C(O)R^(22c),—C(O)OR^(22d), —C(O)N(R^(22e))R^(22f), —N(R^(22g))C(O)R^(22h),—N(R^(22i))C(O)N(R^(22j))R^(22k), —N(R^(22m))S(O)₂R^(21b),—S(O)₂N(R^(22n))R^(22o), —S(O)₂R^(21c), —OS(O)₂R^(21d) and aryl, and anR⁴ substituent in a position on the phenyl or pyridyl group that isortho- to the position at which the group B is attached may (i) togetherwith R^(19a), represent C₂₋₄ alkylene optionally interrupted orterminated by O, S or N(R²⁰), or (ii) together with R^(19b), representC₂₋₄ alkylene; R²⁰ represents H or C₁₋₆ alkyl; R^(21a) to R^(21d),independently represent C₁₋₆ alkyl; R^(22a) and R^(22b), independentlyrepresent H, C₁₋₆ alkyl or together represent C₃₋₆ alkylene, resultingin a four- to seven-membered nitrogen-containing ring; and R^(22c) toR^(22o), independently represent H or C₁₋₆ alkyl; R¹ represents C₁₋₁₂alkyl (which alkyl group is optionally substituted by one or more groupsselected from halo, cyano, nitro, aryl Het¹, —C(O)R^(5a), —OR^(5b),—N(R⁶)R^(5c), —C(O)XR⁷, —C(O)N(R^(8a))R^(5d), —OC(O)N(R^(8b))R^(5e),—S(O)₂R^(9a), —S(O)₂N(R^(9b))R^(9c) and —N(R^(9b))S(O)₂R^(9d)); X is Oor S; R^(5a) to R^(5e), independently, represent at each occurrence whenused herein, H, C₁₋₆ alkyl (which latter group is optionally substitutedby one or more substituents selected from —OH, halo, cyano, nitro, aryl,aryloxy, Het², —S(O)₂N(R^(9b))R^(9c) and —N(R^(9b))S(O)₂R^(9d)), aryl orHet³, or R^(5d) or R^(5e), together with, respectively R^(8a) or R^(8b),may represent C₃₋₆ alkylene (which alkylene group is optionallyinterrupted by an O atom and/or is optionally substituted by one or moreC₁₋₃ alkyl groups); R⁶ represents H, C₁₋₆ alkyl (optionally substitutedby one or more substituents selected from —OH, halo, cyano, nitro, aryl,—S(O)₂N(R^(9b))R^(9c) and —N(R^(9b))S(O)₂R^(9d)), aryl, —C(O)R^(10a),—C(O)OR^(10b), —C(O)N(R^(10c))R^(10d) or —S(O)₂R^(10e); R^(10a) toR^(10e), independently, represent C₁₋₆ alkyl (optionally substituted byone or more substituents selected from —OH, halo, cyano, nitro andaryl), aryl or R^(10a), R^(10c) or R^(10d) represents H; R⁷ represents,at each occurrence when used herein, C₁₋₁₂ alkyl (optionally substitutedby one or more substituents selected from —OH, halo, cyano, nitro, aryl,C₁₋₆ alkoxy Het⁴, —S(O)₂N(R^(9b))R^(9c) and —N(R^(9b))S(O)₂R^(9d));R^(8a) and R^(8b) independently represent H, C₁₋₁₂ alkyl, C₁₋₆ alkoxy(which latter two groups are optionally substituted by one or moresubstituents selected from —OH, halo, cyano, nitro, C₁₋₄ alkyl, C₁₋₄alkoxy, —S(O)₂N(R^(9b))R^(9c) and —N(R^(9b))S(O)₂R^(9d)), -D-aryl,-D-aryloxy, -D-Het⁵, -D-N(H)C(O)R^(11a), -D-S(O)₂R^(12a),-D-C(O)R^(11b), -D-C(O)OR^(12b), -D-C(O)N(R^(11c))R^(11d), or R^(8a) orR^(8b), together with, respectively, R^(5d) or R^(5e), may representC₃₋₆ alkylene (which alkylene group is optionally interrupted by an Oatom and/or is optionally substituted by one or more C₁₋₃ alkyl groups);R^(9a) represents at each occurrence when used herein, C₁₋₆ alkyl(optionally substituted by one or more substituents selected from —OH,halo, cyano, nitro, aryl, —S(O)₂N(R^(9b))R^(9c) and—N(R^(9b))S(O)₂R^(9d)) or aryl; R^(9b) represents at each occurrencewhen used herein H or C₁₋₆ alkyl; R^(9c) and R^(9d), independently,represent at each occurrence when used herein C₁₋₆ alkyl (optionallysubstituted by one or more substituents selected from —OH, halo, cyano,nitro, aryl and Het⁶), aryl or Het⁷, or R^(9c) represents H; R^(11a) toR^(11d), independently, represent H, C₁₋₆ alkyl (optionally substitutedby one or more substituents selected from —OH, halo, cyano, nitro andaryl), aryl, or R^(11c) and R^(11d) together represent C₁₋₆ alkylene;R^(12a) and R^(12b), independently, represent C₁₋₆ alkyl (optionallysubstituted by one or more substituents selected from —OH, halo, cyano,nitro and aryl) or aryl; and D represents at each occurrence when usedherein a direct bond or C₁₋₆ alkylene; wherein each aryl and aryloxygroup unless otherwise specified, is optionally substituted; incombination with another drug for use as a medicament for the treatmentof arrhythmia or a cardiovascular disorder. 40-45. (canceled)
 46. Acompound of claim 39 in combination with an anticoagulant.
 47. Acompound of claim 46 wherein the anticoagulant is a substance selectedfrom aspirin, warfarin, enoxaparin, heparin, low molecular weightheparin, cilostazol, clopidogrel, ticlopidine, tirofiban, abciximab,dipyridamole, plasma protein fraction, human albumin, low molecularweight dextran, hetastarch, reteplase, alteplase, streptokinase,urokinase, dalteparin, filgrastin, immunoglogulin, ginkolide B,hirudins, foropafant, rocepafant, bivalirudin, dermatan sulfatemediolanum, eptilibatide, tirofiban, thrombomodulin, abcxmab, lowmolecular weight dermatan sulfate-opocrin, eptacog alfa, argatroban,fondaparinux sodium, tifacogin, lepirudin, desirudin, OP2000, roxifiban,parnaparin sodium, human hemoglobin, bovine hemoglobin, humanhemoglobin, antithrombin III, RSR 13, heparin-oral transgenicantithrombin III, H37695, enoxaparin sodium, mesoglycan, CTC 111,bivalirudin, or any combination thereof.
 48. A compound of claim 47wherein the anticoagulant is aspirin or warfarin.
 49. A compound ofclaim 46 wherein the anticoagulant is a thrombin inhibitor.
 50. Acompound of claim 49 wherein the thrombin inhibitor is a low molecularweight thrombin inhibitor.
 51. A compound of claim 50 wherein the lowmolecular weight thrombin inhibitor is a low molecular weightpeptide-based, amino acid-based, and/or peptide analogue-based, thrombininhibitor.
 52. A compound of claim 51 wherein the low molecular weightpeptide-based thrombin inhibitor is a gatran.
 53. A compound of claim 52wherein the gatran is inogatran or melagatran.